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Xuan C, Chen D, Zhang S, Li C, Fang Q, Chen D, Liu J, Jiang X, Zhang Y, Shen W, Cai G, Chen X, Li P. Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2414587. [PMID: 40184310 DOI: 10.1002/advs.202414587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/10/2025] [Indexed: 04/06/2025]
Abstract
At the convergence point of multiple cytokine signals, signal transducer and activator of transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, a natural small-molecule inhibitor of STAT3, may have beneficial effects on diabetic nephropathy; however, the underlying mechanism remains unclear. Isoquercitrin significantly mitigated renal inflammation and fibrosis by inhibiting STAT3 activity in mice with diabetic nephropathy. Moreover, STAT3 is a direct molecular target of isoquercitrin, which as corroborated by tight and stable noncovalent binding between them. This interaction is mechanistically supported by the affinity of isoquercitrin for the Ser668-Gln635-Gln633 region within the pY+1 binding pocket of the SH2 domain. This binding obstructs pivotal processes like STAT3 phosphorylation and dimerization, thereby suppressing its transcriptional function. Finally, a kidney-targeted nanocarrier, Iso@PEG-GK, is developed to load isoquercitrin, thus enhancing its therapeutic precision for diabetic nephropathy. Iso@PEG-GK significantly improved the absorption and renal distribution of isoquercitrin. This study is the first to demonstrate that isoquercitrin exerts a significant protective effect against diabetic nephropathy and may provide a novel therapeutic drug for this disease.
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Affiliation(s)
- Chen Xuan
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Donghui Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Shuangna Zhang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Chaofan Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Qingyun Fang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Dinghua Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Jiabao Liu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Xin Jiang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Yingjie Zhang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Wanjun Shen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
| | - Ping Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, 100000, China
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Fogo AB, Harris RC. Crosstalk between glomeruli and tubules. Nat Rev Nephrol 2025; 21:189-199. [PMID: 39643696 DOI: 10.1038/s41581-024-00907-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2024] [Indexed: 12/09/2024]
Abstract
Models of kidney injury have classically concentrated on glomeruli as the primary site of injury leading to glomerulosclerosis or on tubules as the primary site of injury leading to tubulointerstitial fibrosis. However, current evidence on the mechanisms of progression of chronic kidney disease indicates that a complex interplay between glomeruli and tubules underlies progressive kidney injury. Primary glomerular injury can clearly lead to subsequent tubule injury. For example, damage to the glomerular filtration barrier can expose tubular cells to serum proteins, including complement and cytokines, that would not be present in physiological conditions and can promote the development of tubulointerstitial fibrosis and progressive decline in kidney function. In addition, although less well-studied, increasing evidence suggests that tubule injury, whether primary or secondary, can also promote glomerular damage. This feedback from the tubule to the glomerulus might be mediated by changes in the reabsorptive capacity of the tubule, which can affect the glomerular filtration rate, or by mediators released by injured proximal tubular cells that can induce damage in both podocytes and parietal epithelial cells. Examining the crosstalk between the various compartments of the kidney is important for understanding the mechanisms underlying kidney pathology and identifying potential therapeutic interventions.
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Affiliation(s)
- Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Raymond C Harris
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Tennessee Department of Veterans Affairs, Nashville, TN, USA.
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Lundgren M, Ridefelt P, Kristoffersson C, Samuelsson I, Larsson A. Inter-laboratory variation for urine albumin among laboratories in a Swedish external quality assessment scheme 2005-2023. Clin Biochem 2024; 133-134:110825. [PMID: 39299566 DOI: 10.1016/j.clinbiochem.2024.110825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/24/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
INTRODUCTION Increased albuminuria is associated with elevated mortality. Urine albumin (U-ALB) above 20 mg/L or albumin-to-creatinine ratio (U-ACR) of 3 g/mol are indicative of moderately increased albuminuria. Due to limited standardization among U-ALB methods, diagnosis of increased albuminuria might prove difficult. MATERIALS AND METHODS Data from Equalis's external quality assessment scheme for low U-ALB levels during 2005-2023 were categorized according to manufacturer and divided into central laboratory (CLAB) and point-of-care testing (POCT) methods. Manufacturer median values were compared to total group mean consensus values and manufacturer CV% was compared at different U-ALB levels. RESULTS CLAB was generally closer to consensus values and had lower CV% than POCT at U-ALB levels around 20 mg/L. For CLAB, Roche methods were approximately equal to consensus U-ALB, Abbott 4 % above, and Siemens 5 % below. For POCT, HemoCue was 1 % below, Siemens 7 % above, and Abbott 8 % below. For U-Creatinine, all manufacturers generally had a good agreement differing on average by 1-4 % from consensus. CONCLUSIONS Although U-ALB methods generally meet The National Kidney Disease Education Program (NKDEP) recommendations of method bias less than 13 % and imprecision less than 30 %, differences among manufacturers have increased over the last years, with 2023 showing the largest differences between methods. This highlights the need for guidelines for albuminuria and ACR to take method differences into consideration, but also for implementation of suitable urine reference materials.
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Affiliation(s)
- Morgan Lundgren
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sjukhusvägen 7, 753 09 Uppsala, Sweden.
| | - Peter Ridefelt
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sjukhusvägen 7, 753 09 Uppsala, Sweden
| | | | | | - Anders Larsson
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sjukhusvägen 7, 753 09 Uppsala, Sweden
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Edwards A. Renal handling of albumin in rats with early stage diabetes: A theoretical analysis. J Physiol 2024; 602:3575-3592. [PMID: 38857419 PMCID: PMC11250707 DOI: 10.1113/jp286245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/20/2024] [Indexed: 06/12/2024] Open
Abstract
In early diabetic nephropathy (DN), recent studies have shown that albuminuria stems mostly from alterations in tubular function rather than from glomerular damage. Several factors in DN, including hyperfiltration, hypertrophy and reduced abundance of the albumin receptors megalin and cubilin, affect albumin endocytosis in the proximal tubule (PT). To assess their respective contribution, we developed a model of albumin handling in the rat PT that couples the transport of albumin to that of water and solutes. Our simulations suggest that, under basal conditions, ∼75% of albumin is retrieved in the S1 segment. The model predicts negligible uptake in S3, as observed experimentally. It also accurately predicts the impact of acute hyperglycaemia on urinary albumin excretion. Simulations reproduce observed increases in albumin excretion in early DN by considering the combined effects of increased glomerular filtration rate (GFR), osmotic diuresis, hypertrophy, and megalin and cubilin downregulation, without stipulating changes in glomerular permselectivity. The results indicate that in isolation, glucose-elicited osmotic diuresis and glucose transporter upregulation raise albumin excretion only slightly. Enlargement of PT diameter not only augments uptake via surface area expansion, but also reduces fluid velocity and thus shear stress-induced stimulation of endocytosis. Overall, our model predicts that downregulation of megalin and cubilin and hyperfiltration both contribute significantly to increasing albumin excretion in rats with early-stage diabetes. The results also suggest that acute sodium-glucose cotransporter 2 inhibition lowers albumin excretion only if GFR decreases sufficiently, and that angiotensin II receptor blockers mitigate urinary albumin loss in early DN in large part by upregulating albumin receptor abundance. KEY POINTS: The urinary excretion of albumin is increased in early diabetic nephropathy (DN). It is difficult to experimentally disentangle the multiple factors that affect the renal handling of albumin in DN. We developed a mathematical model of albumin transport in the rat proximal tubule (PT) to examine the impact of elevated plasma glucose, hyperfiltration, PT hypertrophy and reduced abundance of albumin receptors on albumin uptake and excretion in DN. Our model predicts that glucose-elicited osmotic diuresis per se raises albumin excretion only slightly. Conversely, increases in PT diameter and length favour reduced albumin excretion. Our results suggest that downregulation of the receptors megalin and cubilin in PT cells and hyperfiltration both contribute significantly to increasing albumin excretion in DN. The model helps to better understand the mechanisms underlying urinary loss of albumin in early-stage diabetes, and the impact of specific treatments thereupon.
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Affiliation(s)
- Aurélie Edwards
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
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Iordan L, Gaita L, Timar R, Avram V, Sturza A, Timar B. The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review. Int J Mol Sci 2024; 25:7057. [PMID: 39000165 PMCID: PMC11241663 DOI: 10.3390/ijms25137057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.
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Affiliation(s)
- Liana Iordan
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Laura Gaita
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Romulus Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Vlad Avram
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Adrian Sturza
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Bogdan Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Silva-Aguiar RP, Teixeira DE, Peruchetti DB, Peres RAS, Alves SAS, Calil PT, Arruda LB, Costa LJ, Silva PL, Schmaier AH, Rocco PRM, Pinheiro AAS, Caruso-Neves C. Toll like receptor 4 mediates the inhibitory effect of SARS-CoV-2 spike protein on proximal tubule albumin endocytosis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167155. [PMID: 38579939 DOI: 10.1016/j.bbadis.2024.167155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/07/2024]
Abstract
Tubular proteinuria is a common feature in COVID-19 patients, even in the absence of established acute kidney injury. SARS-CoV-2 spike protein (S protein) was shown to inhibit megalin-mediated albumin endocytosis in proximal tubule epithelial cells (PTECs). Angiotensin-converting enzyme type 2 (ACE2) was not directly involved. Since Toll-like receptor 4 (TLR4) mediates S protein effects in various cell types, we hypothesized that TLR4 could be participating in the inhibition of PTECs albumin endocytosis elicited by S protein. Two different models of PTECs were used: porcine proximal tubule cells (LLC-PK1) and human embryonic kidney cells (HEK-293). S protein reduced Akt activity by specifically inhibiting of threonine 308 (Thr308) phosphorylation, a process mediated by phosphoinositide-dependent kinase 1 (PDK1). GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect. S protein did not change total TLR4 expression but decreased its surface expression. LPS-RS, a TLR4 antagonist, also counteracted the effects of the S protein on Akt phosphorylation at Thr308, albumin endocytosis, and megalin expression. Conversely, these effects of the S protein were replicated by LPS, an agonist of TLR4. Incubation of PTECs with a pseudovirus containing S protein inhibited albumin endocytosis. Null or VSV-G pseudovirus, used as control, had no effect. LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression.
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Affiliation(s)
- Rodrigo P Silva-Aguiar
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Douglas E Teixeira
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Diogo B Peruchetti
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rodrigo A S Peres
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Sarah A S Alves
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro T Calil
- Paulo de Góes Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luciana B Arruda
- Paulo de Góes Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luciana J Costa
- Paulo de Góes Microbiology Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro L Silva
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Alvin H Schmaier
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Patricia R M Rocco
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Ana Acacia S Pinheiro
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil
| | - Celso Caruso-Neves
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
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Molitoris BA, Dunn KW, Sandoval RM. Proximal tubule role in albumin homeostasis: controversy, species differences, and the contributions of intravital microscopy. Kidney Int 2023; 104:1065-1069. [PMID: 37981429 DOI: 10.1016/j.kint.2023.05.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 05/23/2023] [Accepted: 05/30/2023] [Indexed: 11/21/2023]
Affiliation(s)
- Bruce A Molitoris
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
| | - Kenneth W Dunn
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ruben M Sandoval
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Silva-Aguiar RP, Teixeira DE, Peres RAS, Alves SAS, Novaes-Fernandes C, Dias WB, Pinheiro AAS, Peruchetti DB, Caruso-Neves C. O-Linked GlcNAcylation mediates the inhibition of proximal tubule (Na ++K +)ATPase activity in the early stage of diabetes mellitus. Biochim Biophys Acta Gen Subj 2023; 1867:130466. [PMID: 37742874 DOI: 10.1016/j.bbagen.2023.130466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/11/2023] [Accepted: 09/18/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus (DM). It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling in the early stage of DM and its molecular mechanism. METHODS Streptozotocin (STZ)-induced diabetic BALB/c mice (STZ group) and LLC-PK1 cells, a model of PTECs, were used. All parameters were assessed in the 4th week after an initial injection of STZ. RESULTS Early stage of DKD was characterized by hyperfiltration and PTEC dysfunction. STZ group exhibited increased urinary sodium excretion due to impairment of tubular sodium reabsorption. This was correlated to a decrease in cortical (Na++K+)ATPase (NKA) α1 subunit expression and enzyme activity and an increase in O-GlcNAcylation. RNAseq analysis of patients with DKD revealed an increase in expression of the glutamine-fructose aminotransferase (GFAT) gene, a rate-limiting step of hexosamine biosynthetic pathway, and a decrease in NKA expression. Incubation of LLC-PK1 cells with 10 μM thiamet G, an inhibitor of O-GlcNAcase, reduced the expression and activity of NKA and increased O-GlcNAcylation. Furthermore, 6-diazo-5-oxo-L-norleucine (DON), a GFAT inhibitor, or dapagliflozin, an SGLT2 inhibitor, avoided the inhibitory effect of HG on expression and activity of NKA associated with the decrease in O-GlcNAcylation. CONCLUSION Our results show that the impairment of tubular sodium reabsorption, in the early stage of DM, is due to SGLT2-mediated HG influx in PTECs, increase in O-GlcNAcylation and reduction in NKA expression and activity.
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Affiliation(s)
- Rodrigo P Silva-Aguiar
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Douglas E Teixeira
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rodrigo A S Peres
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Sarah A S Alves
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carolina Novaes-Fernandes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Wagner B Dias
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Acacia S Pinheiro
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health - NanoSAUDE/FAPERJ, Rio de Janeiro, Brazil
| | - Diogo B Peruchetti
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Celso Caruso-Neves
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health - NanoSAUDE/FAPERJ, Rio de Janeiro, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, INCT-Regenera, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCTIC, Rio de Janeiro, Brazil.
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Liu Y, Wang J, Xu F, Zhang S, Cui S, Li Y, Wang X, Zheng H, Li J, Kong Y, Yang J, Jiang X, Chang B. A J-shaped relationship between ketones and the risk of diabetic kidney disease in patients with type 2 diabetes: New insights from a cross-sectional study. Diabetes Obes Metab 2023; 25:3317-3326. [PMID: 37608468 DOI: 10.1111/dom.15231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/24/2023]
Abstract
AIM To investigate the association between circulating β-hydroxybutyric acid (βOHB) and diabetic kidney disease (DKD) risk in patients with type 2 diabetes (T2D). MATERIALS AND METHODS A total of 1388 patients with T2D were recruited. Participants were divided into high and normal βOHB groups. Participants in the normal βOHB group were divided into four subgroups according to βOHB quartile (Q). The relationships of βOHB with DKD and DKD subtype were analysed using chi-square and binary logistic regression. Restricted cubic splines were used to explore the non-linear correlation between βOHB concentration and DKD risk in the total population. RESULTS A higher prevalence of DKD was detected in the high compared with the normal βOHB group (43.3% vs. 33.3%, P = .041). Participants in the Q4 group (βOHB, 0.12-0.30 mM) had the lowest prevalence of DKD (P = .001). In the binary logistic regression model, the multivariable-adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for DKD risk were 2.30 (1.62-3.26) for Q1, 1.80 (1.23-2.62) for Q2 and 1.63 (1.10-2.41) for Q3 relative to Q4 (P < .001). Restricted cubic spline analyses suggested a J-shaped association of circulating βOHB concentration with DKD risk. DKD risk was lowest at a serum βOHB concentration of 0.183 mM (OR, 0.63; 95% CI, 0.52-0.77). CONCLUSIONS A J-shaped relationship between circulating ketone level and DKD risk in patients with T2D was determined. Circulating βOHB in the range of 0.12-0.30 mM was associated with a lower risk of DKD. Further studies are warranted to verify the causality and to elucidate the underlying mechanisms.
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Affiliation(s)
- Ying Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Endocrinology Department, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Fang Xu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Endocrinology Department, Inner Mongolia Baogang Hospital, Third Affiliated Hospital of Inner Mongonia Medical University, Baotou, China
| | - Shuang Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Tianjin Women's and Children's Health Center, Tianjin, China
| | - Shanshan Cui
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Endocrinology Department, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Yongmei Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Xiaoyu Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Endocrinology Department, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Hui Zheng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- Endocrinology Department, TEDA International Cardiovascular Hospital, Tianjin, China
| | - Junfeng Li
- Endocrinology Department, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Yan Kong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Xia Jiang
- Endocrinology Department, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
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10
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Claudio P, Gabriella M. Nephrotic syndrome: pathophysiology and consequences. J Nephrol 2023; 36:2179-2190. [PMID: 37466816 DOI: 10.1007/s40620-023-01697-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 07/20/2023]
Abstract
In patients with kidney disease, nephrotic syndrome can lead to several complications including progressive kidney dysfunction. Proteinuria may lead to the formation of cellular or fibrous crescents with reciprocal development of rapidly progressive glomerulonephritis or focal glomerulosclerosis. Proteinuria may also cause overload and dysfunction of tubular epithelial cells, eventually resulting in tubular atrophy and interstitial fibrosis. Hypoalbuminemia is usually associated with increased risk of mortality and kidney dysfunction. Dyslipidemia may increase the risk of atherosclerotic complications, cause podocyte dysfunction and contribute to vascular thrombosis. Urinary loss of anticoagulants and overproduction of coagulation factors may facilitate a hypercoagulable state. Edema, hypogammaglobulinemia, loss of complement factors, and immunosuppressive therapy can favor infection. Treatment of these complications may reduce their impact on the severity of NS. Nephrotic syndrome is a kidney disorder that can worsen the quality of life and increase the risk of kidney disease progression.
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Affiliation(s)
| | - Moroni Gabriella
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
- Nephrology and Dialysis Division, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
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11
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Xu C, Ha X, Yang S, Tian X, Jiang H. Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms. Front Endocrinol (Lausanne) 2023; 14:1232790. [PMID: 37859992 PMCID: PMC10583558 DOI: 10.3389/fendo.2023.1232790] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/19/2023] [Indexed: 10/21/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.
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Affiliation(s)
- Chengren Xu
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xiaowen Ha
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Shufen Yang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xuefei Tian
- Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Hong Jiang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
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12
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Yin S, Zhou Z, Fu P, Jin C, Wu P, Ji C, Shan Y, Shi L, Xu M, Qian H. Roles of extracellular vesicles in ageing-related chronic kidney disease: demon or angel. Pharmacol Res 2023:106795. [PMID: 37211241 DOI: 10.1016/j.phrs.2023.106795] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/02/2023] [Accepted: 05/16/2023] [Indexed: 05/23/2023]
Abstract
Ageing is a universal and unavoidable phenomenon that significantly increases the risk of developing chronic kidney disease (CKD). It has been reported that ageing is associated with functional disruption and structural damage to the kidneys. Extracellular vesicles (EVs), which are nanoscale membranous vesicles containing lipids, proteins, and nucleic acids, are secreted by cells into the extracellular spaces. They have diverse functions such as repairing and regenerating different forms of ageing-related CKD and playing a crucial role in intercellular communication. This paper reviews the etiology of ageing in CKD, with particular attention paid to the roles of EVs as carriers of ageing signals and anti-ageing therapeutic strategies in CKD. In this regard, the double-edged role of EVs in ageing-related CKD is examined, along with the potential for their application in clinical settings.
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Affiliation(s)
- Siqi Yin
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Zixuan Zhou
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Peiwen Fu
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Chaoying Jin
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
| | - Peipei Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Cheng Ji
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Yunjie Shan
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Linru Shi
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Min Xu
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China.
| | - Hui Qian
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China.
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13
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Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease. Eur J Pharmacol 2023; 942:175521. [PMID: 36681317 DOI: 10.1016/j.ejphar.2023.175521] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
Diabetic kidney disease (DKD) is characterized by progressive impairment of kidney function. It has been postulated that tubule-interstitial injury, associated with tubular albuminuria, precedes glomerular damage in the early stage of DKD. Here, we wanted to determine if the development of tubule-interstitial injury at the early stage of DKD implies modulation of megalin-mediated protein reabsorption in proximal tubule epithelial cells (PTECs) by SGLT2-dependent high glucose influx. Rats with streptozotocin (STZ)-induced diabetes were treated or not with dapagliflozin (DAPA) for 8 weeks. Four experimental groups were generated: (1) CONT, control; (2) DAPA, rats treated with DAPA; (3) STZ, diabetic rats; (4) STZ + DAPA, diabetic rats treated with DAPA. No changes in glomerular structure and function were observed. The STZ group presented proteinuria and albuminuria associated with an increase in the fractional excretion of proteins. A positive correlation between glycemia and proteinuria was found. These phenomena were linked to a decrease in luminal and total megalin expression and, consequently, in albumin reabsorption in PTECs. We also observed tubule-interstitial injury characterized by an increase in urinary tubular injury biomarkers and changes in tubular histomorphometry parameters. In addition, inverse correlations were found between cortical albumin uptake and tubule-interstitial injury or glycemia. All these modifications were attenuated in the STZ + DAPA group. These results suggest that SGLT2-dependent high glucose influx into PTECs promotes a harmful effect on the PTECs, leading to the development of tubular albuminuria and tubule-interstitial injury preceding glomerular damage. These results expand current knowledge on the renoprotective effects of gliflozins.
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14
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Huang Y, Chen S, Dai Q, Zhang H, Liu Y. Correlation between urine vitamin D -binding protein and early -stage renal damage in Type 2 diabetes. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2023; 48:40-48. [PMID: 36935176 PMCID: PMC10930559 DOI: 10.11817/j.issn.1672-7347.2023.210701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Indexed: 03/21/2023]
Abstract
OBJECTIVES The excretion of urinary vitamin D-binding protein (uVDBP) is related to the occurrence and development of early-stage renal damage in patients with Type 2 diabetes (T2DM). This study aims to explore the significance of detecting uVDBP in T2DM patients and its relationship with renal tubules, and to provide a new direction for the early diagnosis of T2DM renal damage. METHODS A total of 105 patients with T2DM, who met the inclusion criteria, were included as a patient group, and recruited 30 individuals as a normal control group. The general information and blood and urine biochemical indicators of all subjects were collected; the levels of uVDBP, and a marker of tubular injury [urine kidney injury molecule 1 (uKIM-1), urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine retinol-binding protein (uRBP)] were detected by enzyme-linked immunosorbent assay. The results were corrected by urinary creatinine (Cr) to uVDBP/Cr, uKIM-1/Cr, uNGAL/Cr and uRBP/Cr. The Pearson's and Spearman's correlation tests were used to analyze the correlation between uVDBP/Cr and urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR) and markers of tubular injury, and multivariate linear regression and receiver operating characteristic curve were used to analyze the correlation between uVDBP/Cr and UACR or eGFR. RESULTS Compared with the normal control group, the uVDBP/Cr level in the patient group was increased (P<0.05), and which was positively correlated with UACR (r=0.774, P<0.01), and negatively correlated with eGFR (r=-0.397, P<0.01). There were differences in the levels of uKIM-1/Cr, uNGAL/Cr, and uRBP/Cr between the 2 groups (all P<0.01). The uVDBP/Cr was positively correlated with uKIM-1/Cr (r=0.752, P<0.01), uNGAL/Cr (r=0.644, P<0.01) and uRBP/Cr (r=0.812, P<0.01). The sensitivity was 90.0% and the specificity was 82.9% (UACR>30 mg/g) for evaluation of uVDBP/Cr on T2DM patients with early-stage renal damage, while the sensitivity was 75.0% and the specificity was 72.6% for evaluation of eGFR on T2DM patients with early-stage renal damage. CONCLUSIONS The uVDBP/Cr can be used as a biomarker in early-stage renal damage in T2DM patients.
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Affiliation(s)
- Yuxi Huang
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013.
- Department of Nephrology, Yueyang Central Hospital, Yueyang Hunan 414000, China.
| | - Sijie Chen
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Qing Dai
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Hao Zhang
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Yan Liu
- Department of Nephrology, Third Xiangya Hospital, Central South University, Changsha 410013.
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15
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Silva-Aguiar RP, Teixeira DE, Peres RAS, Peruchetti DB, Gomes CP, Schmaier AH, Rocco PRM, Pinheiro AAS, Caruso-Neves C. Subclinical Acute Kidney Injury in COVID-19: Possible Mechanisms and Future Perspectives. Int J Mol Sci 2022; 23:ijms232214193. [PMID: 36430671 PMCID: PMC9693299 DOI: 10.3390/ijms232214193] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis.
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Affiliation(s)
- Rodrigo P. Silva-Aguiar
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Douglas E. Teixeira
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Rodrigo A. S. Peres
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Diogo B. Peruchetti
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Carlos P. Gomes
- Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- School of Medicine and Surgery, Federal University of the State of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
| | - Alvin H. Schmaier
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Patricia R. M. Rocco
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21045-900, Brazil
| | - Ana Acacia S. Pinheiro
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21045-900, Brazil
| | - Celso Caruso-Neves
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-617, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Rio de Janeiro 21045-900, Brazil
- Correspondence:
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16
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Comper WD, Vuchkova J, McCarthy KJ. New insights into proteinuria/albuminuria. Front Physiol 2022; 13:991756. [PMID: 36225307 PMCID: PMC9548894 DOI: 10.3389/fphys.2022.991756] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
The fractional clearance of proteins as measured in healthy human subjects increases 10,000–100,000- fold when studied in nephrotic patients. This remarkable increase cannot be accounted for by extracellular biophysical mechanisms centered at the glomerular filtration barrier. Rather, it is the nephron and its combination of filtration and cellular uptake that can provide a plausible explanation of these fractional clearance changes. The nephron has two regions that critically determine the level proteinuria/albuminuria. Glomerular filtration of plasma proteins is primarily a size selective event that is basically unchanged in acquired and genetic kidney disease. The glomerular concepts of ‘charge selectivity’ and of ‘large pores’, previously used to explain proteinuria, are now recognized to be flawed and non-existent. Filtered proteins then encounter downstream two protein receptors of the Park and Maack type associated with the proximal tubular cell. The high capacity receptor is thought to retrieve the majority of filtered proteins and return them to the blood supply. Inhibition/saturation of this pathway in kidney disease may create the nephrotic condition and hypoproteinemia/hypoalbuminemia. Inhibitors of this pathway (possibly podocyte derived) are still to be identified. A relatively small proportion of the filtered protein is directed towards a high affinity, low capacity receptor that guides the protein to undergo lysosomal degradation. Proteinuria in normoproteinemic states is derived by inhibition of this pathway, such as in diabetes. The combination of glomerular sieving, and the degradation and retrieval pathways can quantitatively account for the changes in fractional clearance of proteins in the nephrotic condition. Finally, the general retrieval of filtered protein by the proximal tubular cell focuses on the teleological importance of this cell as this retrieval represents the third pillar of retrieval that this cell participates in (it also retrieves water and salt).
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Affiliation(s)
- Wayne D. Comper
- Salaqua Diagnostics Inc, New York, NY, United States
- *Correspondence: Wayne D. Comper,
| | | | - Kevin J. McCarthy
- Department of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA, United States
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Altered Expression of EMT-Related Factors Snail, Wnt4, and Notch2 in the Short-Term Streptozotocin-Induced Diabetic Rat Kidneys. Life (Basel) 2022; 12:life12101486. [PMID: 36294921 PMCID: PMC9605095 DOI: 10.3390/life12101486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/17/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background: The aim of this study was to determine the expression of epithelial to mesenchymal transition (EMT)-related transcription factors Snail, Wnt4, and Notch2 with key roles in renal fibrosis, in different renal areas of diabetic rats: glomeruli (G), proximal and distal convoluted tubules (PCT; DCT). Methods: Male Sprague Dawley rats were instilled with 55 mg/kg streptozotocin (diabetes mellitus type I model, DM group) or citrate buffer (control group). Kidney samples were collected 2 weeks and 2 months after DM induction and processed for immunohistochemistry. Results: Diabetic animals showed higher Wnt4 kidney expression both 2 weeks and 2 months post-DM induction, while Snail expression significantly increased only 2 weeks after DM initiation (p < 0.0001). We determined significantly higher expression of examined EMT-related genes in different kidney regions in diabetic animals compared with controls. The most substantial differences were observed in tubular epithelial cells in the period of 2 weeks after induction, with higher Snail and Wnt4 expression in PCT and increased Snail and Notch2 expression in DCT of diabetic animals (p < 0.0001; p < 0.001). Conclusion: The obtained results point to the EMT-related factors Snail, Wnt4, and Notch2 as a potential contributor to diabetic nephropathy development and progression. Changes in their expression, especially in PCT and DCT, could serve as diagnostic biomarkers for the early stages of DM and might be a promising novel therapeutic target in this condition.
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Silva-Aguiar RP, Peruchetti DB, Pinheiro AAS, Caruso-Neves C, Dias WB. O-GlcNAcylation in Renal (Patho)Physiology. Int J Mol Sci 2022; 23:ijms231911260. [PMID: 36232558 PMCID: PMC9569498 DOI: 10.3390/ijms231911260] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 12/29/2022] Open
Abstract
Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.
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Affiliation(s)
- Rodrigo P. Silva-Aguiar
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Diogo B. Peruchetti
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Ana Acacia S. Pinheiro
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro 21045-900, Brazil
| | - Celso Caruso-Neves
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
- Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro 21045-900, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro 21941-902, Brazil
| | - Wagner B. Dias
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
- Correspondence:
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Heyman SN, Raz I, Dwyer JP, Weinberg Sibony R, Lewis JB, Abassi Z. Diabetic Proteinuria Revisited: Updated Physiologic Perspectives. Cells 2022; 11:2917. [PMID: 36139492 PMCID: PMC9496872 DOI: 10.3390/cells11182917] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/11/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin-angiotensin axis or of sodium-glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.
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Affiliation(s)
- Samuel N. Heyman
- Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, Jerusalem 9765422, Israel
- Division of Geriatrics, Herzog Hospital, Jerusalem 9765422, Israel
| | - Itamar Raz
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9765422, Israel
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 9124001, Israel
| | - Jamie P. Dwyer
- Clinical and Translational Science Institute, University of Utah Health, Salt Lake City, UT 84112, USA
| | | | - Julia B. Lewis
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Departments of Medicine and Nephrology, Vanderbilt University Medical Center, Nashville, TN 37011, USA
| | - Zaid Abassi
- Department of Physiology and Biophysics, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel
- Department of Laboratory Medicine, Rambam Health Care Campus, Haifa 3109601, Israel
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20
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Xie H, Shi Y, Zhou Y, Liu H. TMBIM6 promotes diabetic tubular epithelial cell survival and albumin endocytosis by inhibiting the endoplasmic reticulum stress sensor, IRE1α. Mol Biol Rep 2022; 49:9181-9194. [PMID: 35857174 DOI: 10.1007/s11033-022-07744-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/25/2022]
Abstract
AIM Reduced albumin reabsorption in proximal tubular epithelial cells (PTECs), resulting from decreased megalin plasma membrane (PM) localization due to prolonged endoplasmic reticulum (ER) stress, potentially contributes to albuminuria in early diabetic kidney disease (DKD). To examine this possibility, we investigated the cytoprotective effect of TMBIM6 in promoting diabetic PTEC survival and albumin endocytosis by attenuating ER stress with an IRE1α inhibitor, KIRA6. METHODS AND RESULTS Renal TMBIM6 distribution and expression were determined by immunohistochemistry, western blotting, and qPCR, whereas tubular injury was evaluated in db/db mice. High-glucose (HG)-treated HK-2 cells were either treated with KIRA6 or transduced with a lentiviral vector for TMBIM6 overexpression. ER stress was measured by western blotting and ER-Tracker Red staining, whereas apoptosis was determined by performing TUNEL assays. Megalin expression was measured by immunofluorescence, and albumin endocytosis was evaluated after incubating cells with FITC-labeled albumin. Tubular injury and TMBIM6 downregulation occurred in db/db mouse renal cortical tissues. Both KIRA6 treatment and TMBIM6 overexpression inhibited ER stress by decreasing the levels of phosphorylated IRE1α, XBP1s, GRP78, and CHOP, and stabilizing ER expansion in HG-treated HK-2 cells. TUNEL assays performed with KIRA6-treated or TMBIM6-overexpressing cells showed a significant decrease in apoptosis, consistent with the significant downregulation of BAX and upregulation of BCL-2, as measured by immunoblotting. Both KIRA6 and TMBIM6 overexpression promoted megalin PM localization and restored albumin endocytosis in HG-treated HK-2 cells. CONCLUSION TMBIM6 promoted diabetic PTEC survival and albumin endocytosis by negatively regulating the IRE1α branch of ER stress.
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Affiliation(s)
- Huidi Xie
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Shi
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ying Zhou
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hongfang Liu
- Department of Nephrology and Endocrinology (A), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Dongzhimen Hospital, Renal Research Institute of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, No. 5, Haiyuncang Alley, Dongcheng District, 100700, Beijing, China.
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21
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Devanath A, Jayakumari S., Seena Sankar, Shubha N. Prakash. Nephrin a biomarker of early glomerular injury in newly diagnosed untreated hypertensive subjects. Biomedicine (Taipei) 2022. [DOI: 10.51248/.v42i3.623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Introduction and Aim: Hypertension and proteinuria is known to cause renal and cardiovascular disease and mortality in patients irrespective of diabetes. It is beneficial to identify proteinuria and probable glomerular injury early to take preventive measures from cardiovascular event. In our study, we aimed to evaluate whether a biomarker such as nephrin can detect early glomerular injury in treatment naïve hypertensive subjects.
Materials and Methods: Forty newly diagnosed, treatment naïve hypertensive subjects were recruited for the study along with 40 normotensive controls after obtaining informed consent and procuring approval from. Institutional Ethics Committee. The hypertensive group was classified as diabetic and non-diabetic hypertensives and compared with apparently healthy controls (normotensive). Urine sample was analyzed for microalbumin, creatinine and nephrin. Blood sample was analyzed for glycated hemoglobin, urea, creatinine, sodium, and potassium. Statistical analysis was performed using ANOVA to compare the groups for various parameters. Odds ratio was calculated.
Results: Hypertensives were sub-grouped based on amount of microalbumin excreted. Urine nephrin excretion was significantly higher in hypertensive subjects than normotensive subjects (nephrin cut-off: 0.09 mg/g of creatinine). Urine nephrin (mg/g) was found to be elevated (median 0.15; interquartile range, 0.12 and 0.17) in hypertensives with normoalbuminuria and it was significantly higher than normotensive subjects (median 0.07; interquartile range, 0.04 and 0.09).
Conclusion: Urine nephrin may be used as a biomarker of early glomerular injury in hypertensive subjects even before microalbuminuria is detected.
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22
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Li N, Zhou H. Sodium-glucose Cotransporter Type 2 Inhibitors: A New Insight into the Molecular Mechanisms of Diabetic Nephropathy. Curr Pharm Des 2022; 28:2131-2139. [PMID: 35718973 DOI: 10.2174/1381612828666220617153331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 03/15/2022] [Indexed: 11/22/2022]
Abstract
Diabetic nephropathy is one of the chronic microvascular complications of diabetes and is a leading cause of end-stage renal disease. Fortunately, clinical trials have demonstrated that sodium-glucose cotransporter type 2 inhibitors could decrease proteinuria and improve renal endpoints and are promising agents for the treatment of diabetic nephropathy. The renoprotective effects of sodium-glucose cotransporter type 2 inhibitors cannot be simply attributed to their advantages in aspects of metabolic benefits, such as glycemic control, lowering blood pressure, and control of serum uric acid, or improving hemodynamics associated with decreased glomerular filtration pressure. Some preclinical evidence suggests that sodium-glucose cotransporter type 2 inhibitors exert their renoprotective effects by multiple mechanisms, including attenuation of oxidative and endoplasmic reticulum stresses, anti-fibrosis and anti-inflammation, protection of podocytes, suppression of megalin function, improvement of renal hypoxia, restored mitochondrial dysfunction and autophagy, as well as inhibition of sodium-hydrogen exchanger 3. In the present study, the detailed molecular mechanisms of sodium-glucose cotransporter type 2 inhibitors with the actions of diabetic nephropathy were reviewed, with the purpose of providing the basis for drug selection for the treatment of diabetic nephropathy.
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Affiliation(s)
- Na Li
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hong Zhou
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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23
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Lidberg KA, Muthusamy S, Adil M, Mahadeo A, Yang J, Patel RS, Wang L, Bammler TK, Reichel J, Yeung CK, Himmelfarb J, Kelly EJ, Akilesh S. Serum Protein Exposure Activates a Core Regulatory Program Driving Human Proximal Tubule Injury. J Am Soc Nephrol 2022; 33:949-965. [PMID: 35197326 PMCID: PMC9063895 DOI: 10.1681/asn.2021060751] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 02/06/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The kidneys efficiently filter waste products while retaining serum proteins in the circulation. However, numerous diseases compromise this barrier function, resulting in spillage of serum proteins into the urine (proteinuria). Some studies of glomerular filtration suggest that tubules may be physiologically exposed to nephrotic-range protein levels. Therefore, whether serum components can directly injure the downstream tubular portions of the kidney, which in turn can lead to inflammation and fibrosis, remains controversial. METHODS We tested the effects of serum protein exposure in human kidney tubule microphysiologic systems and with orthogonal epigenomic approaches since animal models cannot directly assess the effect of serum components on tubules. RESULTS Serum, but not its major protein component albumin, induced tubular injury and secretion of proinflammatory cytokines. Epigenomic comparison of serum-injured tubules and intact kidney tissue revealed canonical stress-inducible regulation of injury-induced genes. Concordant transcriptional changes in microdissected tubulointerstitium were also observed in an independent cohort of patients with proteinuric kidney disease. CONCLUSIONS Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention.
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Affiliation(s)
- Kevin A. Lidberg
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Selvaraj Muthusamy
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Mohamed Adil
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Anish Mahadeo
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Jade Yang
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | | | - Lu Wang
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Theo K. Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington
| | - Jonathan Reichel
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Catherine K. Yeung
- Department of Pharmacy, University of Washington, Seattle, Washington
- Kidney Research Institute, Seattle, Washington
| | - Jonathan Himmelfarb
- Kidney Research Institute, Seattle, Washington
- Nephrology Division, Department of Medicine, University of Washington, Seattle, Washington
| | - Edward J. Kelly
- Department of Pharmaceutics, University of Washington, Seattle, Washington
- Kidney Research Institute, Seattle, Washington
| | - Shreeram Akilesh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
- Kidney Research Institute, Seattle, Washington
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24
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Zhu BT. Biochemical mechanism underlying the pathogenesis of diabetic retinopathy and other diabetic complications in humans: the methanol-formaldehyde-formic acid hypothesis. Acta Biochim Biophys Sin (Shanghai) 2022; 54:415-451. [PMID: 35607958 PMCID: PMC9828688 DOI: 10.3724/abbs.2022012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022] Open
Abstract
Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
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Affiliation(s)
- Bao Ting Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and DevelopmentSchool of MedicineThe Chinese University of Hong KongShenzhen518172China
- Department of PharmacologyToxicology and TherapeuticsSchool of MedicineUniversity of Kansas Medical CenterKansas CityKS66160USA
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25
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Activation of TGR5 Ameliorates Streptozotocin-Induced Cognitive Impairment by Modulating Apoptosis, Neurogenesis, and Neuronal Firing. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3716609. [PMID: 35464765 PMCID: PMC9033389 DOI: 10.1155/2022/3716609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 01/03/2022] [Accepted: 03/08/2022] [Indexed: 12/15/2022]
Abstract
Takeda G protein-coupled receptor 5 (TGR5) is the first known G protein-coupled receptor specific for bile acids and is recognized as a new and critical target for type 2 diabetes and metabolic syndrome. It is expressed in many brain regions associated with memory such as the hippocampus and frontal cortex. Here, we hypothesize that activation of TGR5 may ameliorate streptozotocin- (STZ-) induced cognitive impairment. The mouse model of cognitive impairment was established by a single intracerebroventricular (ICV) injection of STZ (3.0 mg/kg), and we found that TGR5 activation by its agonist INT-777 (1.5 or 3.0 μg/mouse, ICV injection) ameliorated spatial memory impairment in the Morris water maze and Y-maze tests. Importantly, INT-777 reversed STZ-induced downregulation of TGR5 and glucose usage deficits. Our results further showed that INT-777 suppressed neuronal apoptosis and improved neurogenesis which were involved in tau phosphorylation and CREB-BDNF signaling. Moreover, INT-777 increased action potential firing of excitatory pyramidal neurons in the hippocampal CA3 and medial prefrontal cortex of ICV-STZ groups. Taken together, these findings reveal that activation of TGR5 has a neuroprotective effect against STZ-induced cognitive impairment by modulating apoptosis, neurogenesis, and neuronal firing in the brain and TGR5 might be a novel and potential target for Alzheimer's disease.
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26
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Molitoris BA, Sandoval RM, Yadav SPS, Wagner MC. Albumin Uptake and Processing by the Proximal Tubule: Physiologic, Pathologic and Therapeutic Implications. Physiol Rev 2022; 102:1625-1667. [PMID: 35378997 PMCID: PMC9255719 DOI: 10.1152/physrev.00014.2021] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
For nearly 50 years the proximal tubule (PT) has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes. Several genetic diseases, nonselective PT cell defects, chronic kidney disease (CKD), and acute PT injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PT injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism, and transcytosis are being reexamined with the use of techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multireceptor complex that mediates albumin binding and uptake and directs proteins for lysosomal degradation after endocytosis. Albumin transcytosis is mediated by a pH-dependent binding affinity to the neonatal Fc receptor (FcRn) in the endosomal compartments. This reclamation pathway rescues albumin from urinary losses and cellular catabolism, extending its serum half-life. Albumin that has been altered by oxidation, glycation, or carbamylation or because of other bound ligands that do not bind to FcRn traffics to the lysosome. This molecular sorting mechanism reclaims physiological albumin and eliminates potentially toxic albumin. The clinical importance of PT albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussion of genetic disorders and therapeutic considerations.
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Affiliation(s)
- Bruce A. Molitoris
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Dept.of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Ruben M. Sandoval
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Shiv Pratap S. Yadav
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Mark C. Wagner
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
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27
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Molitoris BA, Sandoval RM, Wagner MC. Intravital Multiphoton Microscopy as a Tool for Studying Renal Physiology, Pathophysiology and Therapeutics. Front Physiol 2022; 13:827280. [PMID: 35399274 PMCID: PMC8988037 DOI: 10.3389/fphys.2022.827280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/09/2022] [Indexed: 11/13/2022] Open
Abstract
Intravital multiphoton microscopy has empowered investigators to study dynamic cell and subcellular processes in vivo within normal and disease organs. Advances in hardware, software, optics, transgenics and fluorescent probe design and development have enabled new quantitative approaches to create a disruptive technology pioneering advances in understanding of normal biology, disease pathophysiology and therapies. Offering superior spatial and temporal resolution with high sensitivity, investigators can follow multiple processes simultaneously and observe complex interactions between different cell types, intracellular organelles, proteins and track molecules for cellular uptake, intracellular trafficking, and metabolism in a cell specific fashion. The technique has been utilized in the kidney to quantify multiple dynamic processes including capillary flow, permeability, glomerular function, proximal tubule processes and determine the effects of diseases and therapeutic mechanisms. Limitations include the depth of tissue penetration with loss of sensitivity and resolution due to scattered emitted light. Tissue clearing technology has virtually eliminated penetration issues for fixed tissue studies. Use of multiphoton microscopy in preclinical animal models offers distinct advantages resulting in new insights into physiologic processes and the pathophysiology and treatment of diseases.
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Kozyraki R, Verroust P, Cases O. Cubilin, the intrinsic factor-vitamin B12 receptor. VITAMINS AND HORMONES 2022; 119:65-119. [PMID: 35337634 DOI: 10.1016/bs.vh.2022.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cubilin (CUBN), the intrinsic factor-vitamin B12 receptor is a large endocytic protein involved in various physiological functions: vitamin B12 uptake in the gut; reabsorption of albumin and maturation of vitamin D in the kidney; nutrient delivery during embryonic development. Cubilin is an atypical receptor, peripherally associated to the plasma membrane. The transmembrane proteins amnionless (AMN) and Lrp2/Megalin are the currently known molecular partners contributing to plasma membrane transport and internalization of Cubilin. The role of Cubilin/Amn complex in the handling of vitamin B12 in health and disease has extensively been studied and so is the role of the Cubilin-Lrp2 tandem in renal pathophysiology. Accumulating evidence strongly supports a role of Cubilin in some developmental defects including impaired closure of the neural tube. Are these defects primarily caused by the dysfunction of a specific Cubilin ligand or are they secondary to impaired vitamin B12 or protein uptake? We will present the established Cubilin functions, discuss the developmental data and provide an overview of the emerging implications of Cubilin in the field of cardiovascular disease and cancer pathogenesis.
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Affiliation(s)
- Renata Kozyraki
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France.
| | - Pierre Verroust
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France
| | - Olivier Cases
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France
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Rong Q, Han B, Li Y, Yin H, Li J, Hou Y. Berberine Reduces Lipid Accumulation by Promoting Fatty Acid Oxidation in Renal Tubular Epithelial Cells of the Diabetic Kidney. Front Pharmacol 2022; 12:729384. [PMID: 35069186 PMCID: PMC8766852 DOI: 10.3389/fphar.2021.729384] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 12/15/2021] [Indexed: 12/30/2022] Open
Abstract
Abnormal lipid metabolism in renal tubular epithelial cells contributes to renal lipid accumulation and disturbed mitochondrial bioenergetics which are important in diabetic kidney disease. Berberine, the major active constituent of Rhizoma coptidis and Cortex phellodendri, is involved in regulating glucose and lipid metabolism. The present study aimed to investigate the protective effects of berberine on lipid accumulation in tubular epithelial cells of diabetic kidney disease. We treated type 2 diabetic db/db mice with berberine (300 mg/kg) for 12 weeks. Berberine treatment improved the physical and biochemical parameters of the db/db mice compared with db/m mice. In addition, berberine decreased intracellular lipid accumulation and increased the expression of fatty acid oxidation enzymes CPT1, ACOX1 and PPAR-α in tubular epithelial cells of db/db mice. The mitochondrial morphology, mitochondrial membrane potential, cytochrome c oxidase activity, mitochondrial reactive oxygen species, and mitochondrial ATP production in db/db mice kidneys were significantly improved by berberine. Berberine intervention activated the AMPK pathway and increased the level of PGC-1α. In vitro berberine suppressed high glucose-induced lipid accumulation and reversed high glucose-induced reduction of fatty acid oxidation enzymes in HK-2 cells. Importantly, in HK-2 cells, berberine treatment blocked the change in metabolism from fatty acid oxidation to glycolysis under high glucose condition. Moreover, berberine restored high glucose-induced dysfunctional mitochondria. These data suggested that berberine alleviates diabetic renal tubulointerstitial injury through improving high glucose-induced reduction of fatty acid oxidation, alleviates lipid deposition, and protect mitochondria in tubular epithelial cells.
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Affiliation(s)
- Qingfeng Rong
- Department of Endocrinology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Baosheng Han
- Department of Cardiac Surgery, Shanxi Cardiovascular Hospital, Taiyuan, China
| | - Yafeng Li
- Department of Nephrology, Shanxi Province People's Hospital, Taiyuan, China.,Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China
| | - Haizhen Yin
- Central Laboratory, Shanxi Province People's Hospital, Taiyuan, China
| | - Jing Li
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Yanjuan Hou
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
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30
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Letter regarding normal albuminuria in patients with autopsy-proven advanced diabetic nephropathy. Kidney Int Rep 2022; 7:662. [PMID: 35257085 PMCID: PMC8897483 DOI: 10.1016/j.ekir.2021.12.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 11/22/2022] Open
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31
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Li R, She D, Ye Z, Fang P, Zong G, Zhao Y, Hu K, Zhang L, Lei S, Zhang K, Xue Y. Glucagon-Like Peptide 1 Receptor Agonist Improves Renal Tubular Damage in Mice with Diabetic Kidney Disease. Diabetes Metab Syndr Obes 2022; 15:1331-1345. [PMID: 35519661 PMCID: PMC9064072 DOI: 10.2147/dmso.s353717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 04/22/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE This study aims to investigate the renal protective effect of glucagon-like peptide 1 receptor agonist (GLP-1RA) on improving renal tubular damage in diabetic kidney disease (DKD) and to explore the potential mechanism of GLP-1RA on renal tubular protection. METHODS Long-acting GLP-1RA was used to treat DKD mice for 12 weeks. The label-free quantitative proteomic analysis of renal proteins was conducted to explore the differentially expressed proteins (DEPs) in the renal tissues of the control, DKD and GLP-1RA groups. The DEPs and markers of renal tubular injury were verified by qPCR in vivo and in vitro. The expression of glucagon-likepeptide-1 receptor (GLP-1R) in renal tubules was determined by immunofluorescence staining. RESULTS GLP-1RA treatment significantly improved the tubular damages in kidney tissues of DKD mice and mTEC cells stimulated by high glucose (HG). Proteomics analysis revealed that 30 proteins in kidney tissue were differentially expressed among three groups. Seminal vesicle secretory protein 6 (SVS6) was the most differentially expressed protein in kidney tissues among three groups of mice. The expression changes of Svs6 mRNA in vitro and in vivo detected by qPCR were consistent with the results of proteomic analysis. Furthermore, reduction of Svs6 expression by SVS6 siRNA could attenuate HG-stimulated tubular injury in mTEC cells. Immunofluorescence staining also found that GLP-1R was widely expressed in renal tubules in vitro and in vivo. CONCLUSION GLP-1RA significantly improved renal tubular damage in DKD mice. SVS6 may be a potential therapeutic target for GLP-1RA in the treatment of DKD.
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Affiliation(s)
- Ran Li
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Dunmin She
- Department of Endocrinology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, 225001, People’s Republic of China
| | - Zhengqin Ye
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Ping Fang
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Guannan Zong
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Yong Zhao
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Kerong Hu
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Liya Zhang
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Sha Lei
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Keqin Zhang
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
| | - Ying Xue
- Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People’s Republic of China
- Correspondence: Ying Xue; Keqin Zhang, Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, No. 389, Xincun Road, Shanghai, 200065, People’s Republic of China, Tel +86-021-66111061, Email ;
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Shen S, Ji C, Wei K. Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 13:924299. [PMID: 35837297 PMCID: PMC9273736 DOI: 10.3389/fendo.2022.924299] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/27/2022] [Indexed: 12/14/2022] Open
Abstract
Cellular senescence is frequently evident at etiologic sites of chronic diseases and involves essentially irreversible arrest of cell proliferation, increased protein production, resistance to apoptosis, and altered metabolic activity. Regulated cell death plays a vital role in shaping fully functional organs during the developmental process, coordinating adaptive or non-adaptive responses, and coping with long-term harmful intracellular or extracellular homeostasis disturbances. In recent years, the concept of 'diabetic tubulopathy' has emerged. tubular epithelial cells are particularly susceptible to the derangements of diabetic state because of the virtue of the high energy requirements and reliance on aerobic metabolism render. Hyperglycemia, oxidative stress, persistent chronic inflammation, glucose toxicity, advanced glycation end-products (AGEs) accumulation, lipid metabolism disorders, and lipotoxicity contribute to the cellular senescence and different patterns of regulated cell death (apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis) in tubular epithelial cells. We now explore the 'tubulocentric' view of diabetic kidney disease(DKD). And we summarize recent discoveries regarding the development and regulatory mechanisms of cellular senescence, apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis in the pathogenesis of DKD. These findings provide new perspectives on the mechanisms of DKD and are useful for designing novel therapeutic approaches for the treatment of DKD.
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de Alcantara Santos R, Guzzoni V, Silva KAS, Aragão DS, de Paula Vieira R, Bertoncello N, Schor N, Aimbire F, Casarini DE, Cunha TS. Resistance exercise shifts the balance of renin-angiotensin system toward ACE2/Ang 1-7 axis and reduces inflammation in the kidney of diabetic rats. Life Sci 2021; 287:120058. [PMID: 34673118 DOI: 10.1016/j.lfs.2021.120058] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 09/17/2021] [Accepted: 10/12/2021] [Indexed: 12/24/2022]
Abstract
AIMS We aimed to determine whether resistance training (RT) regulates renal renin-angiotensin system (RAS) components and inflammatory mediators in diabetic rats. MAIN METHODS Male Wistar rats (3 months old) were randomly assigned into four groups: non-trained (NT), trained (T), non-trained + diabetes (NTD) and trained +diabetes (TD). Diabetes was induced by streptozotocin (50 mg/kg, Sigma Chemical Co., St. Louis, MO, USA), before RT protocol. Trained rats performed RT protocol on a 110-cm ladder (8 ladder climbs, once/day, 5 days/week, 8 weeks), carrying a load corresponding to 50-80% of maximum carrying capacity. Blood glucose, albuminuria and urinary volume were measured. Renal levels of angiotensin peptides (angiotensin I, II and 1-7), inflammatory markers, and also the activities of angiotensin-converting enzyme (ACE) and ACE2 were determined. KEY FINDINGS Blood glucose and urinary volume were elevated in diabetic animals, and RT decreased albuminuria, renal Ang I and Ang II levels in diabetic rats. RT shifted the balance of renal RAS toward ACE2/Ang 1-7 axis in TD group, and mitigated the high levels of interleukin (IL)-10, IL-1β and cytokine-induced neutrophil chemoattractant 1 (CINC) in the context of diabetes. Strong positive correlations were found between albuminuria and Ang II, IL-10 and IL-1β. On the other hand, intrarenal Ang 1-7 levels were negatively correlated with IL-10 and IL-1β levels. SIGNIFICANCE RT improved kidney function by modulating intrarenal RAS toward ACE2/Ang 1-7 axis and inflammatory cytokines. RT represents a reasonable strategy to improve the renal complications induced by diabetes, counteracting nephropathy-associated maladaptive responses.
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Affiliation(s)
| | - Vinicius Guzzoni
- Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, Brazil
| | - Kleiton Augusto Santos Silva
- Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil; Department of Biomedical Sciences, University of Missouri, Columbia, MO, USA
| | - Danielle Sanches Aragão
- Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Rodolfo de Paula Vieira
- Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, Brazil
| | - Nádia Bertoncello
- Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, Brazil
| | - Nestor Schor
- Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Flávio Aimbire
- Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, Brazil
| | - Dulce Elena Casarini
- Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Tatiana Sousa Cunha
- Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, Brazil.
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Amatruda M, Gembillo G, Giuffrida AE, Santoro D, Conti G. The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:868. [PMID: 34577791 PMCID: PMC8467670 DOI: 10.3390/medicina57090868] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023]
Abstract
Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.
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Affiliation(s)
- Michela Amatruda
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
- Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, 98125 Messina, Italy
| | - Alfio Edoardo Giuffrida
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Giovanni Conti
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
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Baek J, Pennathur S. Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease. Metabolites 2021; 11:metabo11080469. [PMID: 34436410 PMCID: PMC8400583 DOI: 10.3390/metabo11080469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/11/2021] [Accepted: 07/16/2021] [Indexed: 12/23/2022] Open
Abstract
Metabolic reprogramming is a hallmark of diabetic kidney disease (DKD); nutrient overload leads to increased production of metabolic byproducts that may become toxic at high levels. One metabolic byproduct may be 2-hydroxyglutarate (2-HG), a metabolite with many regulatory functions that exists in both enantiomeric forms physiologically. We quantitatively determined the levels of L and D-2HG enantiomers in the urine, plasma, and kidney cortex of db/db mice, a pathophysiologically relevant murine model of type 2 diabetes and DKD. We found increased fractional excretion of both L and D-2HG enantiomers, suggesting increased tubular secretion and/or production of the two metabolites in DKD. Quantitation of TCA cycle metabolites in db/db cortex suggests that TCA cycle overload and an increase in 2-HG precursor substrate, α-ketoglutarate, drive the increased L and D-2HG production in DKD. In conclusion, we demonstrated increased 2-HG enantiomer production and urinary excretion in murine type 2 DKD, which may contribute to metabolic reprogramming and progression of diabetic kidney disease.
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Affiliation(s)
- Judy Baek
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Subramaniam Pennathur
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA;
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA
- Correspondence:
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Lee JH, Yang FJ, Tsai WY, Lee CT, Liu SY, Yang WS, Tung YC. Serum neutrophil gelatinase-associated lipocalin as a potential biomarker of diabetic kidney disease in patients with childhood-onset type 1 diabetes. J Formos Med Assoc 2021; 121:832-840. [PMID: 34253435 DOI: 10.1016/j.jfma.2021.06.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 06/03/2021] [Accepted: 06/21/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND/PURPOSE Diabetic kidney disease (DKD) is a major complication in patients with type 1 diabetes (T1D). The aim of this study was to evaluate the role of serum neutrophil gelatinase-associated lipocalin (sNGAL) in the early detection of DKD in childhood-onset T1D patients. METHODS A total of 116 patients (mean age, 22.3 ± 6.9 years) with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 were enrolled in this prospective cross-sectional study. Persistent albuminuria (PA) was defined as a urine albumin-to-creatinine ratio ≥ 30 mg/g for at least two consecutive years; non-albuminuria (NA) was defined otherwise. The patients were divided into the adult (Ad) (≥18 years, n = 91) and pediatric (Ped) (<18 years, n = 25) groups and further into the Ad-PA (n = 8), Ad-NA (n = 83), Ped-PA (n = 2), and Ad-NA (n = 23) subgroups. In all groups, the sNGAL level was determined. RESULTS The mean diabetes duration was 14.2 ± 6.1 years, and 8.6% patients had PA. There was no significant difference in sNGAL levels between the PA and NA groups; notably, in adults, the sNGAL level was significantly higher in the Ad-PA than Ad-NA subgroups (P = 0.039). The sNGAL level was negatively correlated with the eGFR in adults (rho -0.41, P < 0.001). Multiple linear regression models showed that higher sNGAL levels in the adult group were independent and significant determinants of a lower eGFR (P < 0.001). CONCLUSION An elevated sNGAL was significantly correlated with a decreased eGFR even in the range of normal to mildly decreased renal function. Thus, it is a potential biomarker of early deterioration of DKD in childhood-onset T1D.
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Affiliation(s)
- Ju-Hao Lee
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Feng-Jung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun Lin Branch, Douliu, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Yu Tsai
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Ting Lee
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Yao Liu
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
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Zhuang A, Yap FYT, Borg DJ, McCarthy D, Fotheringham A, Leung S, Penfold SA, Sourris KC, Coughlan MT, Schulz BL, Forbes JM. The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion (alters structural composition). Endocrinol Diabetes Metab 2021; 4:e00278. [PMID: 34277994 PMCID: PMC8279619 DOI: 10.1002/edm2.278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 05/16/2021] [Accepted: 05/22/2021] [Indexed: 11/17/2022] Open
Abstract
AIMS The accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno-protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno-protection. MATERIALS AND METHODS To examine the effects of increased podocyte oligosaccharyltransferase-48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase-48kDa subunit abundance in podocytes driven by the podocin promoter. RESULTS Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra-resolution microscopy of podocytes revealed denudation of foot processes where there was co-localization of oligosaccharyltransferase-48kDa subunit and advanced glycation end-products. CONCLUSIONS These studies indicate that increased podocyte expression of oligosaccharyltransferase-48 kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
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Affiliation(s)
- Aowen Zhuang
- Glycation and Diabetes ComplicationsMater Research Institute – The University of QueenslandTranslational Research InstituteWoolloongabbaQldAustralia
- Faculty of MedicineUniversity of QueenslandSt LuciaQldAustralia
- Baker Heart and Diabetes InstituteMelbourneVicAustralia
| | | | - Danielle J. Borg
- Glycation and Diabetes ComplicationsMater Research Institute – The University of QueenslandTranslational Research InstituteWoolloongabbaQldAustralia
| | - Domenica McCarthy
- Glycation and Diabetes ComplicationsMater Research Institute – The University of QueenslandTranslational Research InstituteWoolloongabbaQldAustralia
| | - Amelia Fotheringham
- Glycation and Diabetes ComplicationsMater Research Institute – The University of QueenslandTranslational Research InstituteWoolloongabbaQldAustralia
| | - Sherman Leung
- Glycation and Diabetes ComplicationsMater Research Institute – The University of QueenslandTranslational Research InstituteWoolloongabbaQldAustralia
| | | | - Karly C. Sourris
- Baker Heart and Diabetes InstituteMelbourneVicAustralia
- Department of DiabetesCentral Clinical SchoolMonash UniversityMelbourneVicAustralia
| | - Melinda T. Coughlan
- Baker Heart and Diabetes InstituteMelbourneVicAustralia
- Department of DiabetesCentral Clinical SchoolMonash UniversityMelbourneVicAustralia
| | - Benjamin L. Schulz
- School of Chemistry and Molecular BiosciencesUniversity of QueenslandSt LuciaQldAustralia
| | - Josephine M. Forbes
- Glycation and Diabetes ComplicationsMater Research Institute – The University of QueenslandTranslational Research InstituteWoolloongabbaQldAustralia
- Faculty of MedicineUniversity of QueenslandSt LuciaQldAustralia
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Megalin-mediated albumin endocytosis in renal proximal tubules is involved in the antiproteinuric effect of angiotensin II type 1 receptor blocker in a subclinical acute kidney injury animal model. Biochim Biophys Acta Gen Subj 2021; 1865:129950. [PMID: 34144121 DOI: 10.1016/j.bbagen.2021.129950] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/07/2021] [Accepted: 06/10/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Tubule-interstitial injury (TII) is one of the mechanisms involved in the progression of renal diseases with progressive proteinuria. Angiotensin II (Ang II) type 1 receptor blockers (ARBs) have been successfully used to treat renal diseases. However, the mechanism correlating treatment with ARBs and proteinuria is not completely understood. The hypothesis that the anti-proteinuric effect of losartan is associated with the modulation of albumin endocytosis in PT epithelial cells (PTECs) was assessed. METHODS We used a subclinical acute kidney injury animal model (subAKI) and LLC-PK1 cells, a model of PTECs. RESULTS In subAKI, PT albumin overload induced TII development, measured by: (1) increase in urinary lactate dehydrogenase and γ-glutamyltranspeptidase activity; (2) proteinuria associated with impairment in megalin-mediated albumin reabsorption; (3) increase in luminal and interstitial space in tubular cortical segments. These effects were avoided by treating the animals with losartan, an ARB. Using LLC-PK1 cells, we observed that: (1) 20 mg/mL albumin increased the secretion of Ang II and decreased megalin-mediated albumin endocytosis; (2) the effects of Ang II and albumin were abolished by 10-8 M losartan; (3) MEK/ERK pathway is the molecular mechanism underlying the Ang II-mediated inhibitory effect of albumin on PT albumin endocytosis. CONCLUSION Our results show that PT megalin-mediated albumin endocytosis is a possible target during the treatment of renal diseases patients with ARB. GENERAL SIGNIFICANCE The findings obtained in the present work represents a step forward to the current knowledge on about the role of ARBs in the treatment of renal disease.
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Gburek J, Konopska B, Gołąb K. Renal Handling of Albumin-From Early Findings to Current Concepts. Int J Mol Sci 2021; 22:ijms22115809. [PMID: 34071680 PMCID: PMC8199105 DOI: 10.3390/ijms22115809] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/29/2022] Open
Abstract
Albumin is the main protein of blood plasma, lymph, cerebrospinal and interstitial fluid. The protein participates in a variety of important biological functions, such as maintenance of proper colloidal osmotic pressure, transport of important metabolites and antioxidant action. Synthesis of albumin takes place mainly in the liver, and its catabolism occurs mostly in vascular endothelium of muscle, skin and liver, as well as in the kidney tubular epithelium. Long-lasting investigation in this area has delineated the principal route of its catabolism involving glomerular filtration, tubular endocytic uptake via the multiligand scavenger receptor tandem—megalin and cubilin-amnionless complex, as well as lysosomal degradation to amino acids. However, the research of the last few decades indicates that also additional mechanisms may operate in this process to some extent. Direct uptake of albumin in glomerular podocytes via receptor for crystallizable region of immunoglobulins (neonatal FC receptor) was demonstrated. Additionally, luminal recycling of short peptides into the bloodstream and/or back into tubular lumen or transcytosis of whole molecules was suggested. The article discusses the molecular aspects of these processes and presents the major findings and controversies arising in the light of the research concerning the last decade. Their better characterization is essential for further research into pathophysiology of proteinuric renal failure and development of effective therapeutic strategies.
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Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol 2021; 17:319-334. [PMID: 33547417 DOI: 10.1038/s41581-021-00393-8] [Citation(s) in RCA: 319] [Impact Index Per Article: 79.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2021] [Indexed: 01/30/2023]
Abstract
Diabetic kidney disease is the leading cause of kidney failure worldwide; in the USA, it accounts for over 50% of individuals entering dialysis or transplant programmes. Unlike other complications of diabetes, the prevalence of diabetic kidney disease has failed to decline over the past 30 years. Hyperglycaemia is the primary aetiological factor responsible for the development of diabetic kidney disease. Once hyperglycaemia becomes established, multiple pathophysiological disturbances, including hypertension, altered tubuloglomerular feedback, renal hypoxia, lipotoxicity, podocyte injury, inflammation, mitochondrial dysfunction, impaired autophagy and increased activity of the sodium-hydrogen exchanger, contribute to progressive glomerular sclerosis and the decline in glomerular filtration rate. The quantitative contribution of each of these abnormalities to the progression of diabetic kidney disease, as well as their role in type 1 and type 2 diabetes mellitus, remains to be determined. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have a beneficial impact on many of these pathophysiological abnormalities; however, as several pathophysiological disturbances contribute to the onset and progression of diabetic kidney disease, multiple agents used in combination will likely be required to slow the progression of disease effectively.
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Bielopolski D, Rahamimov R, Zingerman B, Chagnac A, Azulay-Gitter L, Rozen Zvi B. Microalbuminuria After Kidney Transplantation Predicts Cardiovascular Morbidity. Front Med (Lausanne) 2021; 8:635847. [PMID: 33912576 PMCID: PMC8071984 DOI: 10.3389/fmed.2021.635847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/08/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Microalbuminuria is a well-characterized marker of kidney malfunction, both in diabetic and non-diabetic populations, and is used as a prognostic marker for cardiovascular morbidity and mortality. A few studies implied that it has the same value in kidney transplanted patients, but the information relies on spot or dipstick urine protein evaluations, rather than the gold standard of timed urine collection. Methods: We revisited a cohort of 286 kidney transplanted patients, several years after completing a meticulously timed urine collection and assessed the prevalence of major cardiovascular adverse events (MACE) in relation to albuminuria. Results: During a median follow up of 8.3 years (IQR 6.4–9.1) 144 outcome events occurred in 101 patients. By Kaplan-Meier analysis microalbuminuria was associated with increased rate of CV outcome or death (p = 0.03), and this was still significant after stratification according to propensity score quartiles (p = 0.048). Time dependent Cox proportional hazard analysis showed independent association between microalbuminuria and CV outcomes 2 years following microalbuminuria detection (HR 1.83, 95% CI 1.07–2.96). Conclusions: Two years after documenting microalbuminuria in kidney transplanted patients, their CVD risk was increased. There is need for primary prevention strategies in this population and future studies should address the topic.
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Affiliation(s)
- Dana Bielopolski
- Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ruth Rahamimov
- Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Boris Zingerman
- Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Avry Chagnac
- Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Limor Azulay-Gitter
- Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Benaya Rozen Zvi
- Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Mbatha B, Khathi A, Sibiya N, Booysen I, Mangundu P, Ngubane P. Anti-hyperglycaemic effects of dioxidovanadium complex cis-[VO 2(obz)py] avert kidney dysfunction in streptozotocin-induced diabetic male Sprague-Dawley rats. Can J Physiol Pharmacol 2021; 99:402-410. [PMID: 33759555 DOI: 10.1139/cjpp-2020-0278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Despite the success of antidiabetic drugs in alleviation of hyperglycaemia, diabetic complications, including renal dysfunction, continue to be a burden. This raises the need to seek alternative therapies that will alleviate these complications. Accordingly, the aim of this study was to investigate the effects of dioxidovanadium(V) complex cis-[VO2(obz)py] on renal function in diabetic rats. Streptozotocin-induced diabetic rats were treated with cis-[VO2(obz)py] (40 mg·kg-1) twice every third day for five weeks. Diabetic untreated and insulin-treated rats served as the diabetic control and positive control, respectively. Blood glucose concentrations, water intake, urinary output, and mean arterial pressure (MAP) were monitored weekly for five weeks. Rats were then euthanized, and blood and kidney tissues were collected for biochemical analysis. Significant decreases in blood glucose concentrations, MAP, glomerular filtration rate (GFR), and SGLT2 expression, as well as plasma angiotensin and aldosterone concentrations, were observed in the treated groups compared with the diabetic control. The complex also increased urinary glucose concentrations, antioxidant enzymes GPx and SOD concentrations, and decreased MDA concentrations and kidney injury molecule (KIM-1) concentrations. These findings suggest that the anti-hyperglycaemic effects of this vanadium complex may ameliorate kidney dysfunction in diabetes.
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Affiliation(s)
- Bonisiwe Mbatha
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Andile Khathi
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Ntethelelo Sibiya
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa
| | - Irvin Booysen
- School of Chemistry and Physics, College of Agriculture, Engineering and Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa
| | - Patrick Mangundu
- School of Chemistry and Physics, College of Agriculture, Engineering and Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa
| | - Phikelelani Ngubane
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
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Dunn KW, Molitoris BA, Dagher PC. The Indiana O'Brien Center for Advanced Renal Microscopic Analysis. Am J Physiol Renal Physiol 2021; 320:F671-F682. [PMID: 33682441 DOI: 10.1152/ajprenal.00007.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The Indiana O'Brien Center for Advanced Microscopic Analysis is a National Institutes of Health (NIH) P30-funded research center dedicated to the development and dissemination of advanced methods of optical microscopy to support renal researchers throughout the world. The Indiana O'Brien Center was founded in 2002 as an NIH P-50 project with the original goal of helping researchers realize the potential of intravital multiphoton microscopy as a tool for understanding renal physiology and pathophysiology. The center has since expanded into the development and implementation of large-scale, high-content tissue cytometry. The advanced imaging capabilities of the center are made available to renal researchers worldwide via collaborations and a unique fellowship program. Center outreach is accomplished through an enrichment core that oversees a seminar series, an informational website, and a biennial workshop featuring hands-on training from members of the Indiana O'Brien Center and imaging experts from around the world.
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Affiliation(s)
- Kenneth W Dunn
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Bruce A Molitoris
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Pierre C Dagher
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Obert LA, Elmore SA, Ennulat D, Frazier KS. A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies. Toxicol Pathol 2021; 49:996-1023. [PMID: 33576319 DOI: 10.1177/0192623320985045] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A host of novel renal biomarkers have been developed over the past few decades which have enhanced monitoring of renal disease and drug-induced kidney injury in both preclinical studies and in humans. Since chronic kidney disease (CKD) and acute kidney injury (AKI) share similar underlying mechanisms and the tubulointerstitial compartment has a functional role in the progression of CKD, urinary biomarkers of AKI may provide predictive information in chronic renal disease. Numerous studies have explored whether the recent AKI biomarkers could improve upon the standard clinical biomarkers, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio, for predicting outcomes in CKD patients. This review is an introduction to alternative assays that can be utilized in chronic (>3 months duration) nonclinical safety studies to provide information on renal dysfunction and to demonstrate specific situations where these assays could be utilized in nonclinical drug development. Novel biomarkers such as symmetrical dimethyl arginine, dickkopf homolog 3, and cystatin C predict chronic renal injury in animals, act as surrogates for GFR, and may predict changes in GFR in patients over time, ultimately providing a bridge from preclinical to clinical renal monitoring.
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Affiliation(s)
- Leslie A Obert
- 549350GlaxoSmithKline (GSK), Nonclinical Safety, Collegeville, PA, USA
| | - Susan A Elmore
- Cellular and Molecular Pathology Branch, National Toxicology Program (NTP), 6857National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Daniela Ennulat
- 549350GlaxoSmithKline (GSK), Nonclinical Safety, Collegeville, PA, USA
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Pafundi PC, Garofalo C, Galiero R, Borrelli S, Caturano A, Rinaldi L, Provenzano M, Salvatore T, De Nicola L, Minutolo R, Sasso FC. Role of Albuminuria in Detecting Cardio-Renal Risk and Outcome in Diabetic Subjects. Diagnostics (Basel) 2021; 11:290. [PMID: 33673215 PMCID: PMC7918197 DOI: 10.3390/diagnostics11020290] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/29/2022] Open
Abstract
The clinical significance of albuminuria in diabetic subjects and the impact of its reduction on the main cardiorenal outcomes by different drug classes are among the most interesting research focuses of recent years. Although nephrologists and cardiologists have been paying attention to the study of proteinuria for years, currently among diabetics, increased urine albumin excretion ascertains the highest cardio-renal risk. In fact, diabetes is a condition by itself associated with a high-risk of both micro/macrovascular complications. Moreover, proteinuria reduction in diabetic subjects by several treatments lowers both renal and cardiovascular disease progression. The 2019 joint ESC-EASD guidelines on diabetes, prediabetes and cardiovascular (CV) disease assign to proteinuria a crucial role in defining CV risk level in the diabetic patient. In fact, proteinuria by itself allows the diabetic patient to be staged at very high CV risk, thus affecting the choice of anti-hyperglycemic drug class. The purpose of this review is to present a clear update on the role of albuminuria as a cardio-renal risk marker, starting from pathophysiological mechanisms in support of this role. Besides this, we will show the prognostic value in observational studies, as well as randomized clinical trials (RCTs) demonstrating the potential improvement of cardio-renal outcomes in diabetic patients by reducing proteinuria.
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Affiliation(s)
- Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Carlo Garofalo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Silvio Borrelli
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Michele Provenzano
- Renal Unit, Department of Health Sciences, “Magna Graecia” University, Viale Europa, 88100 Catanzaro, Italy;
| | - Teresa Salvatore
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via De Crecchio 7, 80138 Naples, Italy;
| | - Luca De Nicola
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Roberto Minutolo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (P.C.P.); (C.G.); (R.G.); (S.B.); (A.C.); (L.R.); (L.D.N.)
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Duan S, Lu F, Song D, Zhang C, Zhang B, Xing C, Yuan Y. Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2021; 12:661185. [PMID: 34177803 PMCID: PMC8223745 DOI: 10.3389/fendo.2021.661185] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/21/2021] [Indexed: 12/29/2022] Open
Abstract
Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.
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Liu X, Zhang X, Cai X, Dong J, Chi Y, Chi Z, Gu HF. Effects of Curcumin on High Glucose-Induced Epithelial-to-Mesenchymal Transition in Renal Tubular Epithelial Cells Through the TLR4-NF-κB Signaling Pathway. Diabetes Metab Syndr Obes 2021; 14:929-940. [PMID: 33688227 PMCID: PMC7936700 DOI: 10.2147/dmso.s296990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/03/2021] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Diabetic kidney disease (DKD) is a microvascular complication in diabetes mellitus, while tubuloepithelial to mesenchymal transition (EMT) of mature tubular epithelial cells is a key point in the early development and progression of renal interstitial fibrosis. The present study aimed to investigate the protective effects of Curcumin on EMT and fibrosis in cultured normal rat kidney tubular epithelial cell line (NRK-52E). METHODS By using immunofluorescence staining and Western blot protocols, in vitro experiments were designed to analyze EMT markers, including collagen I and E-cadherin in high glucose (HG) exposed NRK-52E cells and to detect the expression levels of phosphorylated-NF-κB, TLR4 and reactive oxygen species (ROS) after Curcumin pre-treatment. With co-treatment with TAK242, these molecules in the TLR4-NF-κB signaling pathway were further evaluated. RESULTS Curcumin decreased the HG-induced EMT levels and ROS production in NRK-52E cells. Furthermore, Curcumin was found to inhibit the TLR4-NF-κB signaling activation in HG-induced EMT of NRK-52E cells. CONCLUSION The present study provides evidence suggesting a novel mechanism that Curcumin exerts the anti-fibrosis effects via inhibiting activation of the TLR4-NF-κB signal pathway and consequently protecting the HG-induced EMT in renal tubular epithelial cells. Thereby, TLR4-NF-κB may be a useful target for therapeutic intervention in DKD.
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Affiliation(s)
- Xinhui Liu
- Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, 110847, People’s Republic of China
| | - Xiuli Zhang
- Department of Nephrology, Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of China
- Department of Pathophysiology, China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China
- Correspondence: Xiuli Zhang Department of Nephrology, Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of China Email
| | - Xiaoyi Cai
- Department of Nephrology, Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of China
| | - Jiqiu Dong
- Department of Nephrology, Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, 518000, People’s Republic of China
| | - Yinmao Chi
- Department of Physiology, China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China
| | - Zhihong Chi
- Department of Pathophysiology, China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China
| | - Harvest F Gu
- Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, People’s Republic of China
- Harvest F Gu Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, People’s Republic of China Email
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Feng X, Wang S, Sun Z, Dong H, Yu H, Huang M, Gao X. Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice. Front Endocrinol (Lausanne) 2021; 12:626390. [PMID: 33679620 PMCID: PMC7930496 DOI: 10.3389/fendo.2021.626390] [Citation(s) in RCA: 198] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/06/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Ferroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice. METHODS Db/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice. RESULTS Db/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice. CONCLUSIONS Our study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway.
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Affiliation(s)
- Xiaomeng Feng
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- *Correspondence: Xiaomeng Feng, ; Xia Gao,
| | - Shuo Wang
- Department of Infectious Diseases, Beijing Traditional Chinese Medical Hospital, Capital Medical University, Beijing, China
| | - Zhencheng Sun
- Department of Osteology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Hengbei Dong
- Department of Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Haitian Yu
- Education Division, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Mengxiu Huang
- Department of Hepatobiliary, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xia Gao
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- *Correspondence: Xiaomeng Feng, ; Xia Gao,
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Chaudhari S, Mallet RT, Shotorbani PY, Tao Y, Ma R. Store-operated calcium entry: Pivotal roles in renal physiology and pathophysiology. Exp Biol Med (Maywood) 2020; 246:305-316. [PMID: 33249888 DOI: 10.1177/1535370220975207] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid-base homeostasis. Many of these cells are regulated by Ca2+ signaling. Recent evidence demonstrates that SOCCs are major Ca2+ entry portals in several renal cell types. SOCC is activated by depletion of Ca2+ stores in the sarco/endoplasmic reticulum, which communicates with plasma membrane SOCC via the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Orai1 is recognized as the main pore-forming subunit of SOCC in the plasma membrane. Orai proteins alone can form highly Ca2+ selective SOCC channels. Also, members of the Transient Receptor Potential Canonical (TRPC) channel family are proposed to form heteromeric complexes with Orai1 subunits, forming SOCC with low Ca2+ selectivity. Recently, Ca2+ entry through SOCC, known as store-operated Ca2+ entry (SOCE), was identified in glomerular mesangial cells, tubular epithelium, and renovascular smooth muscle cells. The physiological and pathological relevance and the characterization of SOCC complexes in those cells are still unclear. In this review, we summarize the current knowledge of SOCC and their roles in renal glomerular, tubular and vascular cells, including studies from our laboratory, emphasizing SOCE regulation of fibrotic protein deposition. Understanding the diverse roles of SOCE in different renal cell types is essential, as SOCC and its signaling pathways are emerging targets for treatment of SOCE-related diseases.
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Affiliation(s)
- Sarika Chaudhari
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Robert T Mallet
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Parisa Y Shotorbani
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Yu Tao
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Rong Ma
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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Liu X, Xu C, Xu L, Li X, Sun H, Xue M, Li T, Yu X, Sun B, Chen L. Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway. Metabolism 2020; 111:154334. [PMID: 32777444 DOI: 10.1016/j.metabol.2020.154334] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 08/01/2020] [Accepted: 08/04/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND PURPOSE Excessive mitochondrial fission was observed in diabetic kidney disease (DKD). Phosphoglycerate mutase family member 5 (PGAM5) plays an important role in mitochondrial fission by dephosphorylating the dynamin-related protein 1 at Ser637 (DRP1S637). Whether PGAM5 participates in the mitochondrial fission in diabetic renal tubular injury is unknown. Clinical trials have observed encouraging effect of Sodium-glucose cotransporter 2 (SGLT2) inhibitors on DKD though the underling mechanisms remain unclear. EXPERIMENTAL APPROACH We used KK-Ay mice as diabetic model and Empagliflozin (Empa) were administrated by oral gavage. The mitochondrial fission and the expressions of phosphorylated AMP-activated protein kinase (p-AMPK), specificityprotein1 (SP1), PGAM5 and DRP1S637 were tested. We also examined these changes in HK2 cells that cultured in normal glucose (NG), high glucose (HG) and high glucose+Empa (HG + Empa) environment. Then we verified our deduction using AMPK activator (5-aminoimidazole-4-carboximide Riboside, AICAR), inhibitor (Compound C), si-SP1 and si-PGAM5. Lastly, we testified the interaction between SP1 and the PGAM5promotor by CHIP assay. KEY RESULTS The mitochondrial fission and the expression of SP1, PGAM5 increased and the expression of p-AMPK, DRP1S637 decreased in diabetic or HG environment. These changes were all reversed in Empa or AICAR treated groups. These reversal effects of Empa could be diminished by Compound C. Either si-SP1 or si-PGAM5 could alleviate the mitochondrial fission without affection on AMPK phosphorylation. Finally, the CHIP assay confirmed the interaction between SP1 and the PGAM5 promotor. CONCLUSIONS AND IMPLICATIONS The PGAM5 aggravated the development of diabetic renal tubular injury and the Empa could improve the DKD by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway.
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Affiliation(s)
- Xiangyang Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Chaofei Xu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Linxin Xu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Xiaoyu Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Hongxi Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Mei Xue
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Ting Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Xiaochen Yu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China.
| | - Liming Chen
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital &Tianjin Institute of Endocrinology, Tianjin 300070, China.
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