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Zheng C, Zhang J, Chen X, Zhang J, Ding X, You X, Fan L, Chen C, Zhou Y. MicroRNA-155 Mediates Obesity-Induced Renal Inflammation and Dysfunction. Inflammation 2019; 42:994-1003. [PMID: 30715692 DOI: 10.1007/s10753-019-00961-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Chronic inflammation is a major contributor to obesity-related renal damage. Recent studies have demonstrated that microRNA (miR)-155 is closely associated with hyperglycemia-induced nephropathy, but whether renal miR-155 participates in the inflammatory response and development of obesity-related nephropathy is unknown. In present study, we investigated the pathophysiological role of renal miR-155 in palmitic acid (PA)-treated endothelial cell and high-fat-diet (HFD)-fed mouse models by specific miR-155 sponge. Mice fed with HFD exhibited higher levels of renal miR-155, which positively correlated with urine microalbumin and blood urea nitrogen. In vitro study, mouse renal vascular endothelial cells stimulated with PA also showed higher miR-155 levels, accompanied with increased inflammatory response. Suppression of renal miR-155 effectively attenuated HFD-induced renal structural damages and dysfunction. MiR-155 sponge treatment also significantly decreased NF-κB signaling and downstream gene expression in vitro and in vivo. The obesity-increased macrophage infiltration and lipotoxicity was decreased in mouse kidney after miR-155 sponge treatment. Mechanistically, miR-155 directly targeted 3'-UTR of SHIP1/INPP5D and suppressed its expression in vitro and in vivo, whereas silence of SHIP1/INPP5D abolished the renal protective benefits of miR-155 sponge in obese mice. Taken together, present findings for the first time provided evidence for the potential role of miR-155 in obesity-related nephropathy and clarified that SHIP1/NF-κB signaling was a potential molecular mechanism.
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Affiliation(s)
- Chenfei Zheng
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ji Zhang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xinxin Chen
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jianna Zhang
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaokai Ding
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaohan You
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lin Fan
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Chaosheng Chen
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Ying Zhou
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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White Z, Milad N, Tehrani AY, Chen WWH, Donen G, Sellers SL, Bernatchez P. Angiotensin II receptor blocker losartan exacerbates muscle damage and exhibits weak blood pressure-lowering activity in a dysferlin-null model of Limb-Girdle muscular dystrophy type 2B. PLoS One 2019; 14:e0220903. [PMID: 31404091 PMCID: PMC6690544 DOI: 10.1371/journal.pone.0220903] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 07/25/2019] [Indexed: 01/01/2023] Open
Abstract
There is no cure or beneficial management option for Limb-Girdle muscular dystrophy (MD) type 2B (LGMD2B). Losartan, a blood pressure (BP) lowering angiotensin II (AngII) receptor type 1 (ATR1) blocker (ARB) with unique anti-transforming growth factor-β (TGF-β) properties, can protect muscles in various types of MD such as Duchenne MD, suggesting a potential benefit for LGMD2B patients. Herein, we show in a mild, dysferlin-null mouse model of LGMD2B that losartan increased quadriceps muscle fibrosis (142%; P<0.0001). In a severe, atherogenic diet-fed model of LGMD2B recently described by our group, losartan further exacerbated dysferlin-null mouse muscle wasting in quadriceps and triceps brachii, two muscles typically affected by LGMD2B, by 40% and 51%, respectively (P<0.05). Lower TGF-β signalling was not observed with losartan, therefore plasma levels of atherogenic lipids known to aggravate LGMD2B severity were investigated. We report that losartan increased both plasma triglycerides and cholesterol concentrations in dysferlin-null mice. Other protective properties of losartan, such as increased nitric oxide release and BP lowering, were also reduced in the absence of dysferlin expression. Our data suggest that LGMD2B patients may show some resistance to the primary BP-lowering effects of losartan along with accelerated muscle wasting and dyslipidemia. Hence, we urge caution on the use of ARBs in this population as their ATR1 pathway may be dysfunctional.
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Affiliation(s)
- Zoe White
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
- * E-mail: (ZW); (PB)
| | - Nadia Milad
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
| | - Arash Y. Tehrani
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
| | - William Wei-Han Chen
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
| | - Graham Donen
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
| | - Stephanie L. Sellers
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
| | - Pascal Bernatchez
- University of British Columbia (UBC) Department of Anesthesiology, Pharmacology & Therapeutics, Vancouver, Canada
- UBC Centre for Heart Lung Innovation & St. Paul’s Hospital, Vancouver, Canada
- * E-mail: (ZW); (PB)
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Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease. Int J Mol Sci 2019; 20:ijms20143393. [PMID: 31295940 PMCID: PMC6678414 DOI: 10.3390/ijms20143393] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 06/28/2019] [Accepted: 07/08/2019] [Indexed: 12/22/2022] Open
Abstract
Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents.
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Culshaw GJ, Costello HM, Binnie D, Stewart KR, Czopek A, Dhaun N, Hadoke PWF, Webb DJ, Bailey MA. Impaired pressure natriuresis and non-dipping blood pressure in rats with early type 1 diabetes mellitus. J Physiol 2019; 597:767-780. [PMID: 30537108 PMCID: PMC6355628 DOI: 10.1113/jp277332] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/28/2018] [Indexed: 01/26/2023] Open
Abstract
KEY POINTS Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long-term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow. Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes. ABSTRACT Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague-Dawley rats were injected with streptozotocin (30-45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non-diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non-diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.
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Affiliation(s)
- Geoffrey J. Culshaw
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - Hannah M. Costello
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - David Binnie
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - Kevin R. Stewart
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - Alicja Czopek
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - Neeraj Dhaun
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - Patrick W. F. Hadoke
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - David J. Webb
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
| | - Matthew A. Bailey
- The British Heart Foundation Centre for Cardiovascular ScienceThe Queen's Medical Research InstituteThe University of Edinburgh47 Little France CrescentEdinburghEH16 4TJUK
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Neelofar K, Arif Z, Arafat MY, Alam K, Ahmad J. A study on correlation between oxidative stress parameters and inflammatory markers in type 2 diabetic patients with kidney dysfunction in north Indian population. J Cell Biochem 2018; 120:4892-4902. [PMID: 30260031 DOI: 10.1002/jcb.27763] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 09/06/2018] [Indexed: 02/02/2023]
Abstract
BACKGROUND Research reports support the statement that oxidative stress and inflammation are well-known risk factors for chronic kidney disease (CKD) in patients with diabetes. This study was designed to ascertain the associated role of oxidative stress parameters and inflammatory markers in diabetes and related CKD among the north Indian population. METHODS The study was divided into three groups as healthy subjects (group 1), patients with diabetes without complication (group 2), and with CKD (group 3). Serum levels of malondialdehyde (MDA) and nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR) content were estimated in all individuals. Inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-α were determined by enzyme-linked immuno-sorbent assay. RESULTS MDA, protein carbonyl, and NO were significantly elevated in patients with type 2 diabetes as compared with healthy subjects (P ≤ 0.05). Total thiols content were found to be significantly decreased in patients with diabetes with CKD. The activity of antioxidant enzymes SOD, CAT, and GR showed a significant suppression in patients with type 2 diabetes with or without CKD as compared with healthy subjects. Nevertheless, the levels of proinflammatory cytokines IL-6 and TNF-α were significantly upregulated ( P ≤ 0.05) as compared with healthy subjects. CONCLUSION Determination of antioxidant defense parameters and inflammatory markers contributes to understand the relationship between oxidative stress and inflammation on the development and prevention of chronic kidney disease in Indian patients with diabetes.
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Affiliation(s)
- Km Neelofar
- Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Zarina Arif
- Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Mir Yasir Arafat
- Center for Vascular & Inflammatory Disease, University of Maryland School of Medicine, Baltimore, Maryland
| | - Khursheed Alam
- Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Jamal Ahmad
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J. N. Medical College, Aligarh Muslim University, Aligarh, India
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Maheshwari M, Romero CA, Monu SR, Kumar N, Liao TD, Peterson EL, Carretero OA. Renal Protective Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) in Obese Rats on a High-Salt Diet. Am J Hypertens 2018; 31:902-909. [PMID: 29722788 DOI: 10.1093/ajh/hpy052] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 04/17/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Obesity is a public health problem, associated with salt sensitive hypertension, kidney inflammation, and fibrosis. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a tetra peptide with anti-inflammatory and anti-fibrotic properties. However, its effect on preventing kidney damage in obesity is unknown. We hypothesized that Zucker obese (ZO) rats on a high-salt (HS) diet develop renal damage, inflammation, fibrosis, and this is prevented with Ac-SDKP treatment. METHODS Zucker lean (ZL) and ZO rats (8 weeks old) were treated with Ac-SDKP (1.6 mg/kg/day) while maintained on either a normal-salt (NS; 0.4%) or HS (4%) diet for 8 weeks. Systolic blood pressure (SBP), albuminuria, renal inflammation, and fibrosis were evaluated. RESULTS HS diet increased macrophage infiltration in the kidneys of both ZL and ZO rats but was significantly higher in ZO rats receiving the HS diet (ZL + NS, 13.9 ± 1.3 vs. ZL + HS, 19.14 ± 1.5 and ZO + NS, 25.5 ± 1.4 vs. ZO + HS, 87.8 ± 10.8 cells/mm2; P < 0.05). Ac-SDKP prevented macrophage infiltration in ZO rats (ZO + HS + Ac-SDKP, 32.18 ± 2.4 cells/mm2; P < 0.05). Similarly, glomerulosclerosis, cortical, and medullary interstitial fibrosis were increased in ZO rats fed the HS diet, and Ac-SDKP attenuated these alterations (P < 0.05). SBP was increased in ZO rats fed the HS diet (ZO + NS, 121.3 ± 8.9 vs. ZO + HS, 164 ± 6.9 mm Hg; P < 0.05), and it was significantly decreased with Ac-SDKP treatment (ZO + HS + Ac-SDKP, 144.05 ± 14.1 mm Hg; P = 0.004). Albuminuria was higher in ZO rats than in ZL rats; however, neither HS nor Ac-SDKP treatment affected it. CONCLUSIONS Ac-SDKP treatment in ZO rats fed a HS diet prevented renal damage by reducing inflammation, fibrosis, and SBP.
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Affiliation(s)
- Mani Maheshwari
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Cesar A Romero
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Sumit R Monu
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Nitin Kumar
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Tang-Dong Liao
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Edward L Peterson
- Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA
| | - Oscar A Carretero
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
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Yaribeygi H, Mohammadi MT, Rezaee R, Sahebkar A. Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy. J Cell Biochem 2018; 119:7458-7469. [PMID: 29761900 DOI: 10.1002/jcb.27055] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 04/23/2018] [Indexed: 12/22/2022]
Abstract
Among several pathological mechanisms involved in diabetic nephropathy, oxidative stress, inflammation, and apoptosis play a prominent role. Fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, has markedly improved oxidative stress and inflammatory responses, but there is no evidence about its effects on interleukin-18 (IL-18), NADPH oxidase type 4 (NOX-4), and p53 expression in diabetic kidneys. The aim of this study was to evaluate possible effects of fenofibrate on improving the underlying mechanisms of diabetic nephropathy. Male Wistar rats were randomly divided into four groups namely, normal, normal treated, diabetic and diabetic treated (N = 6). Diabetes was induced by a single dose of streptozotocin (40 mg/kg; IV). Treated animals received fenofibrate for 8 weeks daily (80 mg/kg; po). All groups were sacrificed on day 56 and blood, urine, and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose were assessed. Then, serum levels of malondialdehyde (MDA), nitrate, and glutathione (GLT), as well as the activities of catalase (CAT) and superoxide dismutase (SOD) enzymes were measured. The expression level of NOX-4, IL-18, and p53 proteins at both mRNA and protein levels were evaluated. Diabetes significantly increased albuminuria, free radicals production, inflammation, and apoptosis in non-treated rats while lowered antioxidant capacity. Moreover, diabetes caused histological damages leading to renal failure. Treatment with fenofibrate improved renal function by improving creatinine clearance (P = 0.01) and protein excretion (P = 0.001) and lowering plasma levels of blood urea nitrogen (P = 0.001), creatinine (P = 0.001), and uric acid (P = 0.01). Fenofibrate potentiated antioxidant defense systems by enhancing CAT (P = 0.01) and SOD (P = 0.01) enzymes activities and GLT content (P = 0.01), and reduced oxidative damage by lowering MDA generation (P = 0.02). Fenofibrate also attenuated the expression of NOX-4 (P = 0.05), IL-18 (P = 0.05), and p53 (P = 0.05) at both mRNA and protein levels. In conclusion, treatment with fenofibrate improved renal function by suppression of oxidative stress, attenuation of inflammation, and inhibition of apoptosis.
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Affiliation(s)
- Habib Yaribeygi
- Neurosciences Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Chronic Kidney Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad T Mohammadi
- Chronic Kidney Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ramin Rezaee
- Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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8
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Patel PS, Rifkin IR. Mycophenolate and nephrology. Lupus 2016. [DOI: 10.1177/0961203306071666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Several large, randomized trials have established mycophenolate mofetil (MMF) as an effective immunosuppressant for kidney transplantation. Inhibition of inosine 5′-monophospate dehydrogenase (IMPDH) by MMF appears to have pleiotropic effects on both immune and non-immune cells. In addition to B- and T-cell inhibition, in vitro and in vivo data suggest that MMF also has inhibitory effects on smooth muscle cells, endothelial cells, and myofibroblasts, findings that may be relevant in considering treatment of primary immune mediated kidney diseases. Clinical trials have established the efficacy of MMF for the treatment of lupus nephritis, as discussed in detail elsewhere in this supplement. Although animal studies have provided the rationale for human trials of MMF in primary glomerular diseases, most of the evidence thus far is conflicting or based largely on pilot studies. Data from larger, controlled trials will soon emerge and may clarify the role of MMF in the treatment of these disorders.
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Affiliation(s)
- PS Patel
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - IR Rifkin
- Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
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9
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Gibson WT, Hayden MR. Mycophenolate mofetil and animal models. Lupus 2016. [DOI: 10.1177/0961203306071675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Mycophenolate mofetil (MMF), is the morpholinoethyl ester of mycophenolic acid (MPA). Though initially developed as an anti-rejection treatment, MMF is beginning to find application in more common immune-mediated diseases. MMF has been shown to be effective against transplant-associated vascular disease, lupus and other inflammatory diseases via multiple mechanisms in several animal models. MMF treatment blocks the proliferation of T cells and B cells, attenuates the production of autoreactive IgG and IgM, diminishes complement deposition, and reduces the production of multiple proinflammatory cytokines including TNF-α, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-6 and IL-12. It also increases production of the anti-inflammatory mediator IL-10. In addition, MMF reduces the infiltration of immune cells into sites of inflammation by interfering with the expression of cell-surface molecules critical for this process, including MHC class II, CD40, CD80, CD86, I-A, and ICAM-1. Additional mechanisms involving mannosylation and N-linked glycosylation of cell-surface molecules are only beginning to be investigated. This article will focus on the contribution of animal models of disease as investigational tools in the development of MMF as an immunomodulatory drug. The use of mice, rats, rabbits, monkeys, baboons and interspecific xenografts will be discussed.
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Affiliation(s)
- WT Gibson
- Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - MR Hayden
- Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
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10
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Elsherbiny NM, Al-Gayyar MMH. The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment. Cytokine 2016; 81:15-22. [PMID: 26836949 DOI: 10.1016/j.cyto.2016.01.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/21/2016] [Accepted: 01/24/2016] [Indexed: 12/18/2022]
Abstract
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Nehal M Elsherbiny
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
| | - Mohammed M H Al-Gayyar
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
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Ascha MS, Ascha ML, Hanouneh IA. Management of immunosuppressant agents following liver transplantation: Less is more. World J Hepatol 2016; 8:148-161. [PMID: 26839639 PMCID: PMC4724578 DOI: 10.4254/wjh.v8.i3.148] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/12/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
Immunosuppression in organ transplantation was revolutionary for its time, but technological and population changes cast new light on its use. First, metabolic syndrome (MS) is increasing as a public health issue, concomitantly increasing as an issue for post-orthotopic liver transplantation patients; yet the medications regularly used for immunosuppression contribute to dysfunctional metabolism. Current mainstay immunosuppression involves the use of calcineurin inhibitors; these are potent, but nonspecifically disrupt intracellular signaling in such a way as to exacerbate the impact of MS on the liver. Second, the impacts of acute cellular rejection and malignancy are reviewed in terms of their severity and possible interactions with immunosuppressive medications. Finally, immunosuppressive agents must be considered in terms of new developments in hepatitis C virus treatment, which undercut what used to be inevitable viral recurrence. Overall, while traditional immunosuppressive agents remain the most used, the specific side-effect profiles of all immunosuppressants must be weighed in light of the individual patient.
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12
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Zheng S, Coventry S, Cai L, Powell DW, Jala VR, Haribabu B, Epstein PN. Renal Protection by Genetic Deletion of the Atypical Chemokine Receptor ACKR2 in Diabetic OVE Mice. J Diabetes Res 2016; 2016:5362506. [PMID: 26798651 PMCID: PMC4699014 DOI: 10.1155/2016/5362506] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 09/25/2015] [Accepted: 09/27/2015] [Indexed: 11/29/2022] Open
Abstract
In diabetic nephropathy (DN) proinflammatory chemokines and leukocyte infiltration correlate with tubulointerstitial injury and declining renal function. The atypical chemokine receptor ACKR2 is a chemokine scavenger receptor which binds and sequesters many inflammatory CC chemokines but does not transduce typical G-protein mediated signaling events. ACKR2 is known to regulate diverse inflammatory diseases but its role in DN has not been tested. In this study, we utilized ACKR2(-/-) mice to test whether ACKR2 elimination alters progression of diabetic kidney disease. Elimination of ACKR2 greatly reduced DN in OVE26 mice, an established DN model. Albuminuria was significantly lower at 2, 4, and 6 months of age. ACKR2 deletion did not affect diabetic blood glucose levels but significantly decreased parameters of renal inflammation including leukocyte infiltration and fibrosis. Activation of pathways that increase inflammatory gene expression was attenuated. Human biopsies stained with ACKR2 antibody revealed increased staining in diabetic kidney, especially in some tubule and interstitial cells. The results demonstrate a significant interaction between diabetes and ACKR2 protein in the kidney. Unexpectedly, ACKR2 deletion reduced renal inflammation in diabetes and the ultimate response was a high degree of protection from diabetic nephropathy.
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Affiliation(s)
- Shirong Zheng
- Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA
- *Shirong Zheng:
| | - Susan Coventry
- Department of Pathology, University of Louisville, Louisville, KY 40202, USA
| | - Lu Cai
- Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA
| | - David W. Powell
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Venkatakrishna R. Jala
- Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA
| | - Bodduluri Haribabu
- Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA
| | - Paul N. Epstein
- Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA
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13
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Toth-Manikowski S, Atta MG. Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets. J Diabetes Res 2015; 2015:697010. [PMID: 26064987 PMCID: PMC4430644 DOI: 10.1155/2015/697010] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 04/17/2015] [Indexed: 12/13/2022] Open
Abstract
Diabetes is a worldwide epidemic that has led to a rise in diabetic kidney disease (DKD). Over the past two decades, there has been significant clarification of the various pathways implicated in the pathogenesis of DKD. Nonetheless, very little has changed in the way clinicians manage patients with this disorder. Indeed, treatment is primarily centered on controlling hyperglycemia and hypertension and inhibiting the renin-angiotensin system. The purpose of this review is to describe the current understanding of how the hemodynamic, metabolic, inflammatory, and alternative pathways are all entangled in pathogenesis of DKD and detail the various therapeutic targets that may one day play a role in quelling this epidemic.
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Affiliation(s)
- Stephanie Toth-Manikowski
- Division of Nephrology, Johns Hopkins University, 1830 E. Monument Street, Suite 416, Baltimore, MD 21287, USA
| | - Mohamed G. Atta
- Division of Nephrology, Johns Hopkins University, 1830 E. Monument Street, Suite 416, Baltimore, MD 21287, USA
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14
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Wang C, Blough E, Arvapalli R, Dai X, Triest WE, Leidy JW, Masannat Y, Wu M. Acetaminophen attenuates glomerulosclerosis in obese Zucker rats via reactive oxygen species/p38MAPK signaling pathways. Free Radic Biol Med 2015; 81:47-57. [PMID: 25614458 DOI: 10.1016/j.freeradbiomed.2015.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 12/05/2014] [Accepted: 01/11/2015] [Indexed: 01/09/2023]
Abstract
Focal segmental glomerulosclerosis is a critical pathological lesion in metabolic syndrome-associated kidney disease that, if allowed to proceed unchecked, can lead to renal failure. However, the exact mechanisms underlying glomerulosclerosis remain unclear, and effective prevention strategies against glomerulosclerosis are currently limited. Herein, we demonstrate that chronic low-dose ingestion of acetaminophen (30 mg/kg/day for 6 months) attenuates proteinuria, glomerulosclerosis, podocyte injury, and inflammation in the obese Zucker rat model of metabolic syndrome. Moreover, acetaminophen treatment attenuated renal fibrosis and the expression of profibrotic factors (fibronectin, connective tissue growth factor, transforming growth factor β), reduced inflammatory cell infiltration into the glomeruli, and decreased the expression of monocyte chemoattractant protein, glutathione (GSH) reductase, and nuclear factor erythroid 2-related factor 2, but increased the level of GSH synthetase in obese animals. Further in vivo and in vitro studies using human renal mesangial cells exposed to high glucose or hydrogen peroxide suggested that the renoprotective effects of acetaminophen are characterized by diminished renal oxidative stress and p38MAPK hyperphosphorylation.
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Affiliation(s)
- Cuifen Wang
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Southeast University, Nanjing, Jiangsu, China
| | - Eric Blough
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA.
| | - Ravikumar Arvapalli
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA
| | - Xiaoniu Dai
- Southeast University, Nanjing, Jiangsu, China
| | | | - John W Leidy
- Huntington VA Medical Center, Huntington, WV 25704, USA
| | - Yanal Masannat
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Huntington, WV 25755, USA
| | - Miaozong Wu
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Department of Internal Medicine, Joan C. Edwards School of Medicine, Huntington, WV 25755, USA.
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15
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García-García PM, Getino-Melián MA, Domínguez-Pimentel V, Navarro-González JF. Inflammation in diabetic kidney disease. World J Diabetes 2014; 5:431-443. [PMID: 25126391 PMCID: PMC4127580 DOI: 10.4239/wjd.v5.i4.431] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 02/24/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus entails significant health problems worldwide. The pathogenesis of diabetes is multifactorial, resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events, with metabolic and hemodynamic alterations. In this context, inflammation has emerged as a key pathophysiology mechanism. New pathogenic pathways will provide targets for prevention or future treatments. This review will focus on the implications of inflammation in diabetes mellitus, with special attention to inflammatory cytokines.
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16
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Shikata K, Makino H. Microinflammation in the pathogenesis of diabetic nephropathy. J Diabetes Investig 2014; 4:142-9. [PMID: 24843643 PMCID: PMC4019266 DOI: 10.1111/jdi.12050] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/19/2022] Open
Abstract
Diabetic nephropathy is the leading cause of end‐stage renal failure in developed countries. Furthermore, diabetic nephropathy is related to the risk of cardiovascular diseases and an increase in mortality of diabetic patients. Several factors are involved in the development of nephropathy, including glomerular hyperfiltration, oxidative stress, accumulation of advanced glycation end‐products, activation of protein kinase C, acceleration of the polyol pathway and over‐expression of transforming growth factor‐β. Recently, accumulated data have emphasized the critical roles of chronic low‐grade inflammation, ‘microinflammation’, in the pathogenesis of diabetic nephropathy, suggesting that microinflammation is a common mechanism in the development of diabetic vascular complications. Expression of cell adhesion molecules, chemokines and pro‐inflammatory cytokines are increased in the renal tissues of diabetic patients and animals. Deficiency of pro‐inflammatory molecules results in amelioration of renal injuries after induction of diabetes in mice. Plasma and urinary levels of cytokines, chemokines and cell adhesion molecules, are elevated and correlated with albuminuria. Several kinds of drugs that have anti‐inflammatory actions as their pleiotropic effects showed renoprotective effects on diabetic animals. Modulation of the inflammatory process prevents renal insufficiency in diabetic animal models, suggesting that microinflammation is one of the promising therapeutic targets for diabetic nephropathy, as well as for cardiovascular diseases.
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Affiliation(s)
- Kenichi Shikata
- Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan ; Department of Medicine and Clinical Science Okayama University Graduate School of Medicine Dentistry, and Pharmaceutical Science Okayama Japan
| | - Hirofumi Makino
- Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan ; Department of Medicine and Clinical Science Okayama University Graduate School of Medicine Dentistry, and Pharmaceutical Science Okayama Japan
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17
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Schmaderer C, Kemmner S, Burkhardt K, Heemann U, Baumann M. Serum myeloid-related protein 8/14 complex is associated with microalbuminuria in patients with type 2 diabetes. Ther Adv Cardiovasc Dis 2014; 8:80-88. [PMID: 24667921 DOI: 10.1177/1753944714528270] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES Microalbuminuria (MA) is associated independently with cardiovascular risk and progression of renal disease in patients with diabetes and the normal population. MA is an accepted factor for microvascular defects, in particular in patients with diabetes, and is associated with inflammation. Activated transmigrating macrophages are key cells in these inflammatory processes. Based on the theory that myeloid-related protein 8/14 complex (MRP8/14) is secreted by transmigrating macrophages, we hypothesized that MA was accompanied by elevated MRP8/14 and investigated whether MA predicts MRP8/14 in patients with type 2 diabetes. METHODS A total of 86 men with type 2 diabetes were grouped according to urinary albumin excretion in normoalbuminuria and MA. Serum MRP8/14 levels were measured by enzyme-linked immunosorbent assay. Established cardiovascular risk factors were quantified in both groups and compared with urinary albumin excretion. RESULTS Albuminuria (mg/day) was positively associated with MRP8/14 (r = 0.34) and systemic blood pressure (r = 0.33). Patients with type 2 diabetes and MA demonstrated significantly higher MRP8/14 levels than patients with normoalbuminuria [median (interquartile range), 1.24 (0.97-2.28) µg/ml versus 0.97 (0.67-1.35) µg/ml, p < 0.05]. Serum creatinine levels, systolic blood pressure (SBP), very low density lipoprotein levels and the incidence of hypertension and coronary artery disease were significantly higher in the group with MA. Both groups did not differ significantly in other cardiovascular risk factors. MA was an independent predictor of serum MRP8/14 levels (β = 0.454) as well as SBP (β = 0.625) and haemoglobin A1c (β = 0.322). CONCLUSION Our data demonstrate that albumin excretion is associated with the process of macrophage activation determined by MRP8/14 levels. These data not only suggest tissue inflammation as a factor for elevated cardiovascular risk in patients with type 2 diabetes, they further point to a role of macrophage activation in this process.
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Affiliation(s)
- Christoph Schmaderer
- Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Stephan Kemmner
- Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Germany
| | | | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Marcus Baumann
- Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Germany
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18
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Human umbilical mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis. Am J Med Sci 2014; 346:486-93. [PMID: 23514668 DOI: 10.1097/maj.0b013e3182831777] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Previous studies have suggested the potential of mesenchymal stem cells (MSCs) to repair damaged kidney diseases. However, the effect of human umbilical cord MSCs (HuMSCs) on the progression of focal segmental glomerulosclerosis (FSGS) remains poorly understood. Adriamycin-induced nephropathy is a rodent model of chronic kidney disease that has been studied extensively and has enabled a greater understanding of the processes underlying the progression of FSGS. This study aimed to investigate the role of HuMSCs on the progression of kidney disease using a model of adriamycin-induced nephropathy. Human MSCs were labeled with 5-bromo-2'-deoxyuridine to track their localization to the kidneys after infusion. Clinical parameters and histology suggested amelioration of FSGS in MSC-treated animals at 12 weeks, especially in those that received repeated doses. These results were associated with reduced serum interleukin (IL)-6 and tumor necrosis factor-α, transforming growth factor-β levels, connective tissue growth factor messenger RNA expression and upregulated serum IL-10 levels. In short, this experiment found that HuMSCs improved kidney fibrosis and modulated the inflammatory response, suggesting that xenogenic transplantation of HuMSCs is a novel approach for improving the progression of FSGS and may be a promising therapeutic intervention in the future.
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19
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Wang L, Li Q, Wang L, Li C, Yang H, Wang X, Tao H. The role of Th17/IL-17 in the pathogenesis of primary nephrotic syndrome in children. Kidney Blood Press Res 2013; 37:332-45. [PMID: 24247026 DOI: 10.1159/000350161] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND This work aims to explore the role of Th17 and IL-17 signaling in the pathogenesis of primary nephrotic syndrome (PNS) in children and podocyte injury, children with PNS were divided into minimal change nephrotic syndrome (MCNS) and non-minimal change nephrotic syndrome [NMCNS, including mesangial proliferative glomerulonephritis (MsPGN) and focal segmental glomerulosclerosis (FSGS)]. METHODS Flow cytometry (FCM) was used to observe the circulating frequency of Th17 cells and the apoptosis of podocytes by annexinV-FITC/PI. Serum IL-1β and IL-6 levels were measured using enzyme-linked immunosorbent assay. The Fas and FasL expressions in podocytes were examined by FCM analysis using a direct immunofluorescence method. Reverse transcription polymerase chain reaction was applied to measure the mRNA expressions of RORc, IL-23p19, Nephrin, WT1, Synaptopodin, Podocalyxin, Fas, and FasL. The IL-17 and IL-1β expression in renal biopsy tissue was detected by immunohistochemistry. The expressions of WT1, Caspase 8, and Caspase 3 in podocyte cell culture were also measured using immunocytochemistry. RESULTS Circulating frequencies of Th17 cells, mRNA levels of RORc and IL-23p19, and serum levels of IL-6 and IL-1β were higher in the MCNS and NMCNS groups than in the control group (all P < 0.05), and were higher in the NMCNS group than in the MCNS group (all P < 0.05). The expressions of IL-17 and IL-1β in renal biopsy tissue were higher in the MCNS, MsPGN, and FSGS groups than in the control group (all P < 0.05). Recombinant murine IL-17 (rmIL-17) had no effect on the expressions of Nephrin, Synaptopodin, and WT1 of mouse podocytes, but caused an decrease in the expression of podocalyxin as well as promoted apoptosis in a dose- and time-dependent fashion. Moreover, rmIL-17 increased the expression of Fas, Casepase-8, and Casepase-3, but had no effect on that of FasL. CONCLUSION Th17/IL-17 may contribute to the pathogenesis of PNS by decreasing the podocalyxin level and inducing podocyte apoptosis.
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Affiliation(s)
- Li Wang
- Department of Nephroimmunology, Children's Hospital of Chongqing Medical University, Chongqing 400014, People's Republic of China
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20
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Abstract
Chronic and acute renal diseases, irrespective of the initiating cause, have inflammation and immune system activation as a common underlying mechanism. The purpose of this review is to provide a broad overview of immune cells and inflammatory proteins that contribute to the pathogenesis of renal disease, and to discuss some of the physiological changes that occur in the kidney as a result of immune system activation. An overview of common forms of acute and chronic renal disease is provided, followed by a discussion of common therapies that have anti-inflammatory or immunosuppressive effects in the treatment of renal disease.
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Affiliation(s)
- John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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21
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Lee W, Eom DW, Jung Y, Yamabe N, Lee S, Jeon Y, Hwang YR, Lee JH, Kim YK, Kang KS, Kim SN. Dendrobium moniliforme Attenuates High-Fat Diet-Induced Renal Damage in Mice through the Regulation of Lipid-Induced Oxidative Stress. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 40:1217-28. [DOI: 10.1142/s0192415x12500905] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Obesity is an important and preventable risk factor for renal disease. The administration of an antioxidant with a lipid-lowering effect is an important therapeutic approach for kidney disease in obese patients. The present study was conducted to examine whether methanolic extract of Dendrobium moniliforme (DM), one of the most famous traditional medicines used in many parts of the world, has an antioxidant effect in vitro and an ameliorative effect on high-fat diet (HFD)-induced alterations such as renal dysfunction and lipid accumulation in vivo. The 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of DM extract (IC50 = 29.6 μg/mL) was increased in a dose-dependent manner. The LLC-PK1 kidney cell damage induced by oxidative stress was significantly inhibited by the treatments with DM extract. In the animal study, DM extract (200 mg/kg) was orally administered every day for nine weeks to HFD-fed mice, and its effect was compared with that of metformin. The administration of DM extract decreased the elevated serum glucose, total cholesterol concentration and renal lipid accumulation in HFD-fed mice. It also ameliorated renal dysfunction biomarkers including serum creatinine and renal collagen IV deposition. Taken together, these results provide important evidence that DM extract exhibits a pleiotropic effect on obesity induced parameters and exerted a renoprotective effect in HFD-fed mice.
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Affiliation(s)
- Woojung Lee
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Dae-Woon Eom
- Department of Pathology, University of Ulsan College of Medicine, Gangneung 210-711, Korea
| | - Yujung Jung
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Noriko Yamabe
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Seungyong Lee
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Youngsic Jeon
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Ye Ran Hwang
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Ji Hwan Lee
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Yong Kee Kim
- College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Korea
| | - Ki Sung Kang
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
| | - Su-Nam Kim
- Natural Medicine Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea
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22
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Vasdev S, Stuckless J, Richardson V. Role of the immune system in hypertension: modulation by dietary antioxidants. Int J Angiol 2012. [PMID: 23204821 DOI: 10.1055/s-0031-1288941] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hypertension is a major health problem worldwide. Individuals with hypertension are at an increased risk for stroke, heart disease, and kidney failure. Although the etiology of essential hypertension has a genetic component, lifestyle factors such as diet play an important role. Insulin resistance is a common feature of hypertension in both humans and animal models affecting glucose and lipid metabolism producing excess aldehydes including methylglyoxal. These aldehydes react with proteins to form conjugates called advanced glycation end products (AGEs). This alters protein structure and function and can affect vascular and immune cells leading to their activation and secretion of inflammatory cytokines. AGEs also act via receptors for advanced glycation end products on these cells altering the function of antioxidant and metabolic enzymes, and ion channels. This results in an increase in cytosolic free calcium, decrease in nitric oxide, endothelial dysfunction, oxidative stress, peripheral vascular resistance, and infiltration of vascular and kidney tissue with inflammatory cells leading to hypertension. Supplementation with dietary antioxidants including vitamins C, E, or B(6), thiols such as cysteine and lipoic acid, have been shown to lower blood pressure and plasma inflammatory cytokines in animal models and humans with essential hypertension. A well-balanced diet rich in antioxidants that includes vegetables, fruits, low fat dairy products, low salt, and includes whole grains, poultry, fish and nuts, lowers blood pressure and vascular inflammation. These antioxidants may achieve their antihypertensive and anti-inflammatory/immunomodulatory effects by reducing AGEs and improving insulin resistance and associated alterations. Dietary supplementation with antioxidants may be a beneficial, inexpensive, front-line alterative treatment modality for hypertension.
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Affiliation(s)
- Sudesh Vasdev
- Discipline of Medicine, Health Sciences Centre, Memorial University, St. John's, Newfoundland, Canada
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23
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Doria A, Niewczas MA, Fiorina P. Can existing drugs approved for other indications retard renal function decline in patients with type 1 diabetes and nephropathy? Semin Nephrol 2012; 32:437-44. [PMID: 23062984 PMCID: PMC3474984 DOI: 10.1016/j.semnephrol.2012.07.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mounting evidence from human, animal, and in vitro studies indicates that existing drugs, developed to treat other disorders, also might be effective in preventing or slowing the progression of diabetic nephropathy to end-stage renal disease. Examples of such drugs include the urate-lowering agent allopurinol, the anti-tumor necrosis factor agents etanercept and infliximab, and the immunomodulating drug abatacept. Because some of these medications are already on the market and have been used for a number of years for other indications, they can be tested immediately in human beings for a beneficial effect on renal function in diabetes. Special emphasis should be placed on evaluating the use of these drugs early in the course of diabetic nephropathy when renal damage is most likely to be reversible and interventions can yield the greatest delay to end-stage renal disease.
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Affiliation(s)
- Alessandro Doria
- Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston
- Harvard Medical School, Boston, USA
| | - Monika A. Niewczas
- Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston
- Harvard Medical School, Boston, USA
| | - Paolo Fiorina
- Harvard Medical School, Boston, USA
- Transplantation Research Center (TRC), Nephrology Division, Children’s Hospital and Brigham and Women's Hospital
- San Raffaele Scientific Institute, Milan, Italy
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24
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Zhang G, Li Q, Wang L, Chen Y, Zhang W, Yang H. The effects of inflammation on lipid accumulation in the kidneys of children with primary nephrotic syndrome. Inflammation 2012; 34:645-52. [PMID: 21103916 DOI: 10.1007/s10753-010-9274-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study aimed to characterize the relationship between inflammation and lipid accumulation in children with primary nephrotic syndrome (PNS). Local expression of interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), low-density lipoprotein receptor (LDLr), sterol regulatory element binding protein-2 (SREBP-2), SREBP cleavage-activating protein (SCAP), and apolipoprotein B100 (apoB100) was analyzed by immunohistochemistry in kidney tissues obtained from children with PNS. Renal histopathology was evaluated by hematoxylin and eosin and periodic acid-Schiff staining. Serum levels of IL-1β and TGF-β1 were measured by enzyme-linked immunosorbent assays. Expression of IL-1β, TGF-β1, LDLr, SREBP-2, SCAP, and apoB100 was higher in samples from patients with non-minimal change necrotic syndrome (NMCNS) compared to both controls and patients with minimal change necrotic syndrome. Deposition of apoB100 was significantly correlated with expression of IL-1β, TGF-β1, LDLr, SREBP-2, and SCAP and with the glomerulosclerosis index, but not with plasma lipid levels. Expression of IL-1β and TGF-β1 was significantly correlated with expression of LDLr, SREBP-2, and SCAP. These findings suggest that inflammation leads to lipid accumulation in the kidney through disruption of the expression of proteins in the SCAP/SREBP-2/LDLr signaling pathway, which may underlie glomerulosclerosis and tubulointerstitial fibrosis in NMCNS.
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Affiliation(s)
- Gaofu Zhang
- Department of Nephroimmunology, Children's Hospital of Chongqing Medical University, Chongqing, 136 Zhongshan Er Road, Yu Zhong District, Chongqing, 400014, People's Republic of China
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25
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Yang W, Wang J, Shi L, Yu L, Qian Y, Liu Y, Wang W, Cheng S. Podocyte injury and overexpression of vascular endothelial growth factor and transforming growth factor-beta 1 in adriamycin-induced nephropathy in rats. Cytokine 2012; 59:370-6. [PMID: 22579701 DOI: 10.1016/j.cyto.2012.04.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 03/19/2012] [Accepted: 04/11/2012] [Indexed: 11/25/2022]
Abstract
The aim of this study is to investigate the expression of nephrin, vascular endothelial growth factor (VEGF), transforming growth factor-beta 1 (TGF-β1), and podocyte number in adriamycin (ADR)-induced nephropathy. A total of 60 male Sprague-Dawley rats were randomly divided into the control group and the ADR nephropathy group. The nephropathy was induced by tail-vein injection of ADR (4 mg/kg) twice at a 14-day interval. The expression levels of nephrin, VEGF, and TGF-β1 in glomeruli were assessed by immunohistochemistry and western blotting. The podocyte number was also evaluated after anti-Wilms' tumor-1 (WT1) immunohistochemical staining. In addition, the urinary protein content, biochemical parameters in serum samples and glomerular sclerosis index (SI) were compared between groups. In the ADR nephropathy group, the expression levels of nephrin was significantly decreased with the fusion of podocyte foot processes at 6 weeks after the first ADR injection, which was associated with a marked proteinuria. A decrease in podocyte number and an increase in SI with the overexpression of both VEGF and TGF-β1 were also observed in the glomeruli at 10 weeks after the first ADR injection. This was associated with focal segmental glomerulosclerosis (FSGS). The study data suggest that podocyte injury and decreased nephrin, as well as increased VEGF and TGF-β1, may contribute to the development of proteinuria and FSGS in ADR-induced nephropathy in rats.
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Affiliation(s)
- Weina Yang
- Department of Anatomy, Histology & Embryology, Medicine School of Xi'an Jiaotong University, Xi'an, PR China
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26
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Conway BR, Rennie J, Bailey MA, Dunbar DR, Manning JR, Bellamy CO, Hughes J, Mullins JJ. Hyperglycemia and renin-dependent hypertension synergize to model diabetic nephropathy. J Am Soc Nephrol 2011; 23:405-11. [PMID: 22193383 DOI: 10.1681/asn.2011060577] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocin-induced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in human diabetic nephropathy. In conclusion, although induction of diabetes alone in rodents has limited utility to model human diabetic nephropathy, renin-dependent hypertension and hyperglycemia synergize to recapitulate many of the clinical, histological, and gene expression changes observed in humans.
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Affiliation(s)
- Bryan R Conway
- MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.
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Gordon J, Kopp JB. Off the beaten renin-angiotensin-aldosterone system pathway: new perspectives on antiproteinuric therapy. Adv Chronic Kidney Dis 2011; 18:300-11. [PMID: 21782136 DOI: 10.1053/j.ackd.2011.06.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 05/31/2011] [Accepted: 06/01/2011] [Indexed: 01/23/2023]
Abstract
CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin-angiotensin-aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin-angiotensin-aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria.
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Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011; 7:327-40. [DOI: 10.1038/nrneph.2011.51] [Citation(s) in RCA: 797] [Impact Index Per Article: 56.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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High-calorie diet with moderate protein restriction prevents cachexia and ameliorates oxidative stress, inflammation and proteinuria in experimental chronic kidney disease. Clin Exp Nephrol 2010; 14:536-47. [PMID: 20820841 DOI: 10.1007/s10157-010-0340-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2010] [Accepted: 08/02/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND In earlier studies we found that a high-fat, high-energy diet (HFED) attenuates proteinuria, azotemia and lipid accumulation in the remnant kidney of rats subjected to 5/6 nephrectomy. This study was conducted to explore the mechanism of the salutary effect of HFED in association with moderate protein restriction in this model. METHODS The 5/6 nephrectomized male rats were randomized to receive regular rat chow (CRF group, n = 6) or HFED diet (CRF + HFED, n = 7) for 12 weeks. Sham-operated rats served as controls (n = 6). RESULTS The CRF group exhibited azotemia, hypertension, proteinuria, diminished body weight, oxidative stress, glomerulosclerosis, tubulo-interstitial inflammation and upregulation of pro-oxidant [NAD(P)H oxidase], pro-inflammatory (NF-κB activation, increased MCP-1, lipoxygenase, ICAM-1, VCAM-1), pro-fibrotic (TGF-β, CTGF) and pro-apoptotic pathways (Bax, caspase-3) in the remnant kidney. Consumption of the HFED resulted in a 66% increment in lipid intake, 8% increment in carbohydrate intake and a 24% reduction in protein intake. The CRF + HFED group gained weight normally, had increments in leptin and adiponectin levels, and despite increments in plasma cholesterol and fatty acids, showed significant attenuation of oxidative stress, proteinuria and inflammation, and partial reversal of the remnant kidney upregulation of pro-oxidant, pro-inflammatory, pro-fibrotic and pro-apoptotic pathways. CONCLUSION Consumption of high-energy diet in association with mild protein restriction results in suppression of upregulated pathways that drive progression of renal injury in the remnant kidney model. These findings may have relevance in the management of chronic kidney disease in humans.
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Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther 2010; 30:49-59. [PMID: 20718759 DOI: 10.1111/j.1755-5922.2010.00218.x] [Citation(s) in RCA: 454] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The prevalence of diabetes has dramatically increased worldwide due to the vast increase in the obesity rate. Diabetic nephropathy is one of the major complications of type 1 and type 2 diabetes and it is currently the leading cause of end-stage renal disease. Hyperglycemia is the driving force for the development of diabetic nephropathy. It is well known that hyperglycemia increases the production of free radicals resulting in oxidative stress. While increases in oxidative stress have been shown to contribute to the development and progression of diabetic nephropathy, the mechanisms by which this occurs are still being investigated. Historically, diabetes was not thought to be an immune disease; however, there is increasing evidence supporting a role for inflammation in type 1 and type 2 diabetes. Inflammatory cells, cytokines, and profibrotic growth factors including transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1), connective tissue growth factor (CTGF), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-18 (IL-18), and cell adhesion molecules (CAMs) have all been implicated in the pathogenesis of diabetic nephropathy via increased vascular inflammation and fibrosis. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species are a primary candidate. Thus, targeting oxidative stress-inflammatory cytokine signaling could improve therapeutic options for diabetic nephropathy. The current review will focus on understanding the relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy to help elucidate the question of which comes first in the progression of diabetic nephropathy, oxidative stress, or inflammation.
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Affiliation(s)
- Ahmed A Elmarakby
- Department of Oral Biology, Medical College of Georgia, Augusta, GA, USA Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA, USA Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
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Vitamin A deficiency results in dysregulation of lipid efflux pathway in rat kidney. Pediatr Nephrol 2010; 25:1435-44. [PMID: 20480185 DOI: 10.1007/s00467-010-1532-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2009] [Revised: 03/03/2010] [Accepted: 03/25/2010] [Indexed: 10/19/2022]
Abstract
The mechanisms of action of vitamin A deficiency (VAD) on lipid metabolism in the rat kidney were investigated in adult female rats and their offspring. The rats were randomized into three groups: (1) control, in which the mother and offspring received a normal diet (4000 retinol IU/kg diet) for 8 weeks; (2) VAD group, in which the mothers and offspring received a VAD diet (400 retinol IU/kg diet) for 8 weeks; (3) vitamin A-refed group, in which a group of pups on a VAD diet for 8 weeks received a complete diet (6500 retinol IU/kg diet) for 15 days. The lipid metabolism of the offsprings' kidneys and its relation to the expression of apolipoprotein B100 (Apo-B100), liver X receptor alpha (LXRalpha), and retinoid X receptor-alpha/beta (RXRalpha/beta) mRNA was analyzed. VAD was found to alter renal lipid metabolism and its immune environment due to the expression of Apo-B100. Compared with the control, VAD rats had significantly higher levels of transforming growth factor-beta 1 and lower levels of ABCA1, a key gene involved in cholesterol efflux and tissue lipid homeostasis. The expression of LXRalpha and RXRalpha/beta mRNA also decreased in the VAD rat kidney. Vitamin A refeeding reversed all of the changes. Lipid metabolism involved in renal reverse cholesterol transport may be mediated by decreasing the signaling through the ABCA1 cholesterol efflux pathway, which is significantly modified in kidneys of vitamin A-deficient rats.
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Sharkey D, Gardner DS, Symonds ME, Budge H. Maternal nutrient restriction during early fetal kidney development attenuates the renal innate inflammatory response in obese young adult offspring. Am J Physiol Renal Physiol 2009; 297:F1199-207. [PMID: 19759269 DOI: 10.1152/ajprenal.00303.2009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Obesity is an independent risk factor for developing chronic kidney disease. Toll-like receptor 4 (TLR4), interleukin (IL)-18, and uncoupling protein 2 (UCP2) are important components of the innate immune system mediating inflammatory renal damage. Early to midgestation maternal nutrient restriction appears to protect the kidney from the deleterious effects of early onset obesity, although the mechanisms remain unclear. We examined the combined effects of gestational maternal nutrient restriction during early fetal kidney development and early onset obesity on the renal innate immune response in offspring. Pregnant sheep were randomly assigned to a normal (control, 100%) or nutrient-restricted (NR, 50%) diet from days 30 to 80 gestation and 100% thereafter. Offspring were killed humanely at 7 days or, following rearing in an obesogenic environment, at 1 yr of age, and renal tissues were collected. IL-18 and TLR4 expression were strongly correlated irrespective of intervention. Seven-day NR offspring had significantly lower relative renal mass and IL-18 mRNA expression. At 1 yr of age, obesity resulted in increased mRNA abundance of TLR4, IL-18, and UCP2, coupled with tubular atrophy and greater immunohistological staining of glomerular IL-6 and medullary tumor necrosis factor (TNF)-alpha. NR obese offspring had a marked reduction of TLR4 abundance and renal IL-6 staining. In conclusion, maternal nutrient restriction during early fetal kidney development attenuates the effects of early onset obesity-related nephropathy, in part, through the downregulation of the innate inflammatory response. A better understanding of maternal nutrition and the in utero nutritional environment may offer therapeutic strategies aimed at reducing the burden of later kidney disease.
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Affiliation(s)
- Don Sharkey
- Early Life Nutrition Research Group, Academic Child Health, University of Nottingham, Nottingham, United Kingdom
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Tarabra E, Giunti S, Barutta F, Salvidio G, Burt D, Deferrari G, Gambino R, Vergola D, Pinach S, Perin PC, Camussi G, Gruden G. Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes 2009; 58:2109-18. [PMID: 19587356 PMCID: PMC2731530 DOI: 10.2337/db08-0895] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Monocyte chemoattractant protein-1 (MCP-1), a chemokine binding to the CC chemokine receptor 2 (CCR2) and promoting monocyte infiltration, has been implicated in the pathogenesis of diabetic nephropathy. To assess the potential relevance of the MCP-1/CCR2 system in the pathogenesis of diabetic proteinuria, we studied in vitro if MCP-1 binding to the CCR2 receptor modulates nephrin expression in cultured podocytes. Moreover, we investigated in vivo if glomerular CCR2 expression is altered in kidney biopsies from patients with diabetic nephropathy and whether lack of MCP-1 affects proteinuria and expression of nephrin in experimental diabetes. RESEARCH DESIGN AND METHODS Expression of nephrin was assessed in human podocytes exposed to rh-MCP-1 by immunofluorescence and real-time PCR. Glomerular CCR2 expression was studied in 10 kidney sections from patients with overt nephropathy and eight control subjects by immunohistochemistry. Both wild-type and MCP-1 knockout mice were made diabetic with streptozotocin. Ten weeks after the onset of diabetes, albuminuria and expression of nephrin, synaptopodin, and zonula occludens-1 were examined by immunofluorescence and immunoblotting. RESULTS In human podocytes, MCP-1 binding to the CCR2 receptor induced a significant reduction in nephrin both mRNA and protein expression via a Rho-dependent mechanism. The MCP-1 receptor, CCR2, was overexpressed in the glomerular podocytes of patients with overt nephropathy. In experimental diabetes, MCP-1 was overexpressed within the glomeruli and the absence of MCP-1 reduced both albuminuria and downregulation of nephrin and synaptopodin. CONCLUSIONS These findings suggest that the MCP-1/CCR2 system may be relevant in the pathogenesis of proteinuria in diabetes.
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Affiliation(s)
- Elena Tarabra
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | - Sara Giunti
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
- Emergency Medicine Division, Umberto Parini Hospital, Aosta, Italy
| | - Federica Barutta
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | | | - Davina Burt
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | | | - Roberto Gambino
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | | | - Silvia Pinach
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | - Paolo Cavallo Perin
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | - Giovanni Camussi
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
| | - Gabriella Gruden
- Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Italy
- Corresponding author: Gabriella Gruden,
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An WS, Kim HJ, Cho KH, Vaziri ND. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. Am J Physiol Renal Physiol 2009; 297:F895-903. [PMID: 19656915 DOI: 10.1152/ajprenal.00217.2009] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g.kg(-1).day(-1) by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-beta, Smad2, alpha-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-kappaB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox), p22(phox)), PAI-1, TGF-beta, connective tissue growth factor, alpha-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-kappaB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.
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Affiliation(s)
- Won Suk An
- Div. of Nephrology and Hypertension, UCI Medical Center, 101 The City Drive, Bldg. 53, Rm. 125, Rt. 81, Orange, CA 92868, USA
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Su H, Gunter JH, de Vries M, Connor T, Wanyonyi S, Newell FS, Segal D, Molero JC, Reizes O, Prins JB, Hutley LJ, Walder K, Whitehead JP. Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity. Biochem Biophys Res Commun 2009; 386:351-5. [PMID: 19523919 DOI: 10.1016/j.bbrc.2009.06.040] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 06/08/2009] [Indexed: 11/30/2022]
Abstract
We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.
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Affiliation(s)
- Hua Su
- Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia
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Lee EY, Chung CH, Khoury CC, Yeo TK, Pyagay PE, Wang A, Chen S. The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-beta, increases podocyte motility and albumin permeability. Am J Physiol Renal Physiol 2009; 297:F85-94. [PMID: 19420107 DOI: 10.1152/ajprenal.90642.2008] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert noninflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-beta (TGF-beta) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-beta type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-beta-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-beta were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF-beta signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria.
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Affiliation(s)
- Eun Young Lee
- Division of Nephrology/Hypertension, Northwestern University, Chicago, Illinois 60611, USA
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Cho KH, Kim HJ, Rodriguez-Iturbe B, Vaziri ND. Niacin ameliorates oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic renal failure. Am J Physiol Renal Physiol 2009; 297:F106-13. [PMID: 19420110 DOI: 10.1152/ajprenal.00126.2009] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Significant reduction of renal mass causes progressive deterioration of renal function and structure which is mediated by systemic and glomerular hypertension, hyperfiltration, oxidative stress, inflammation, and dyslipidemia. Niacin is known to improve lipid metabolism and exert antioxidant/anti-inflammatory actions. Therefore, we considered that niacin supplementation may attenuate oxidative stress, inflammation, and tissue injury in the remnant kidney. To this end, 56 nephrectomized [chronic kidney disease (CKD)] rats were randomly assigned to niacin-treated (50 mg x kg(-1) x day(-1) in the drinking water for 12 wk) and untreated groups. Sham-operated rats served as controls. The untreated CKD rats exhibited azotemia, hypertension, hypertriglyceridemia, proteinuria, glomerulosclerosis, tubulointerstitial damage, upregulation of MCP-1, plasminogen activator inhibitor-1 (PAI-1), transforming growth factor (TGF)-beta, cyclooxygenase (COX)-1, COX-2, and NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox) and p22(phox) subunits) and activation of NF-kappaB (IkappaB phosphorylation). Niacin administration reduced MCP-1, PAI-1, TGF-beta, p47(phox), p22(phox), COX-1, and NF-kappaB activation, ameliorated hypertension, proteinuria, glomerulosclerosis, and tubulointerstitial injury. Although niacin lowered serum creatinine and raised creatinine clearance, the differences did not reach statistical significance. Thus niacin supplementation helps to attenuate histological injury and mitigate upregulation of oxidative and inflammatory systems in the remnant kidney.
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Affiliation(s)
- Kyu-hyang Cho
- Division of Nephrology and Hypertension, University of California, Irvine, California, USA
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Hong JH, Lee IS. Effects of Artemisia capillaris ethyl acetate fraction on oxidative stress and antioxidant enzyme in high-fat diet induced obese mice. Chem Biol Interact 2009; 179:88-93. [DOI: 10.1016/j.cbi.2008.12.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Revised: 12/04/2008] [Accepted: 12/04/2008] [Indexed: 12/28/2022]
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Abstract
Concurrent with the global obesity epidemic, there is an increasing number of people of all ages developing chronic kidney disease associated with obesity. In adults, the definition of obesity is a BMI greater than 30 kg/m2. Whereas, in children, a BMI greater than the 85th percentile for age is considered overweight and greater than the 95th percentile is classified as obese. Clinical and pathologic characteristics of a distinct nephropathy have emerged independent of that of diabetic or hypertensive glomerulosclerosis. These include a silent presentation in an obese individual with heavy proteinuria, normal serum albumin and the absence of edema. Renal pathologic findings are notable for mesangial matrix expansion, glomerular hypertrophy and reduced density of podocytes with detachment of foot processes from the glomerular basement membrane. These findings are frequently associated with the development of secondary focal segmental glomerulosclerosis. Obesity alone does not appear to be the sole mediator of this nephropathy. It is most likely the ‘second hit’ for individuals who have congenital or acquired reduced nephron mass as well as an inherited genetic vulnerability to the metabolic consequences imposed by cytokines released by adipose tissue. In children, those born of low birthweight, whether small for gestational age and/or preterm, are likely to have reduced nephron mass as well as an increased tendency for early insulin resistance and the development of obesity and the metabolic syndrome. This in turn is perpetuated by the practice of feeding high-calorie fortified formulas to low-birthweight infants. Rapid catch-up growth, early obesity and insulin resistance are major contributors to the emergence of obesity-related glomerulopathy in children and adolescents. Early detection requires recognizing the demographics of high-risk infants and monitoring them for the development of hypertension, elevated glomerular filtration rate, hyperfiltration and proteinuria. After 6 months of age, angiotensin-blocking agents may be used to control blood pressure, glomerular hyperfiltration and proteinuria. If obesity is present, a comprehensive program of weight loss, including diet and exercise, should be the mainstay of treatment. In older children and adolescents, lipid-lowering medications may be indicated. With morbid obesity, bariatric surgery may be an option.
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Affiliation(s)
| | - Maria M Rodríguez
- Director of Pediatric Pathology University of Miami, 2142 Holtz Ctr-JMH East Twr, Miami, FL 33136, USA
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Navarro-González JF, Jarque A, Muros M, Mora C, García J. Tumor necrosis factor-alpha as a therapeutic target for diabetic nephropathy. Cytokine Growth Factor Rev 2009; 20:165-73. [PMID: 19251467 DOI: 10.1016/j.cytogfr.2009.02.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Activation of innate immunity with the subsequent development of a chronic low-grade inflammatory response is now recognized as a critical factor in the pathogenesis of diabetes mellitus and diabetic complications, including diabetic nephropathy. In the setting of diabetic nephropathy, there is now evidence of the relevant contribution of pro-inflammatory cytokines, with special participation of tumor necrosis factor-alpha (TNF-alpha). This new pathogenic perspective leads to new therapeutic implications derived from modulation of inflammation and inflammatory cytokines. Experimental studies have shown the beneficial renal actions derived from TNF-alpha inhibition with the use of soluble TNF-alpha receptor fusion proteins, chimeric monoclonal antibodies and pentoxifylline (PTF). Clinical application of this strategy is nowadays limited to PTF administration, which has demonstrated significant beneficial effects in patients with diabetic nephropathy. Overall, these studies indicate that inhibition of TNF-alpha might be an efficacious treatment for renal disease secondary to diabetes mellitus.
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Affiliation(s)
- Juan F Navarro-González
- Nephrology Service, Univeristy Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
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Hughson MD, Gobe GC, Hoy WE, Manning RD, Douglas-Denton R, Bertram JF. Associations of Glomerular Number and Birth Weight With Clinicopathological Features of African Americans and Whites. Am J Kidney Dis 2008; 52:18-28. [DOI: 10.1053/j.ajkd.2008.03.023] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Accepted: 03/31/2008] [Indexed: 12/24/2022]
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Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol 2008; 294:F697-701. [PMID: 18272603 DOI: 10.1152/ajprenal.00016.2008] [Citation(s) in RCA: 328] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Despite current therapies, many diabetic patients will suffer from declining renal function in association with progressive kidney inflammation. Recently, animal model studies have demonstrated that kidney macrophage accumulation is a critical factor in the development of diabetic nephropathy. However, specific anti-inflammatory strategies are not yet being considered for the treatment of patients with diabetic renal injury. This review highlights the chemokine monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine ligand 2 as a major promoter of inflammation, renal injury, and fibrosis in diabetic nephropathy. Researchers have found that diabetes induces kidney MCP-1 production and that urine MCP-1 levels can be used to assess renal inflammation in this disease. In addition, genetic deletion and molecular blocking studies in rodents have identified MCP-1 as an important therapeutic target for treating diabetic nephropathy. Evidence also suggests that a polymorphism in the human MCP-1 gene is associated with progressive kidney failure in type 2 diabetes, which may identify patients at higher risk who need additional therapy. These findings provide a strong rationale for developing specific therapies against MCP-1 and inflammation in diabetic nephropathy.
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Affiliation(s)
- G H Tesch
- Dept. of Nephrology, Monash Medical Centre, 246 Clayton Rd., Clayton, Victoria 3168, Australia.
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Zhang W, Li Q, Wang L, Yang X. Simvastatin ameliorates glomerulosclerosis in Adriamycin-induced-nephropathy rats. Pediatr Nephrol 2008; 23:2185-94. [PMID: 18791746 PMCID: PMC7811526 DOI: 10.1007/s00467-008-0933-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2007] [Revised: 06/01/2008] [Accepted: 06/03/2008] [Indexed: 12/23/2022]
Abstract
The aim of this study was to investigate the effects of simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, on inflammation and glomerulosclerosis in Adriamycin (ADR)-induced nephropathy. Male Sprague-Dawley rats were randomly divided into control, ADR nephrosis, and simvastatin-treated ADR nephrosis groups. ADR nephropathy was induced by a single-tail intravenous injection of ADR (6.5 mg/kg). Anti-inflammatory effects of simvastatin were studied by evaluating the expression of the inflammatory mediators interleukin-1 beta (IL-1beta), transforming growth factor-beta1 (TGF-beta1), and transcription factor nuclear factor kappa B (NF-kappaB). In addition, renal function, serum lipid levels, and histopathology were compared between groups. Simvastatin significantly decreases IL-1beta and TGF-beta1 expression and NF-kappaB activation, accompanied by significant attenuation of glomerulosclerosis and renal function at 12 weeks after ADR injection, and these changes occurred in the absence of lowering of serum lipids. These results suggest that overexpression of inflammation in the renal region may contribute to development of glomerulosclerosis in ADR-induced-nephropathy rats, and simvastatin treatment prevented glomerulosclerosis independent of the lipid-lowering effects. The beneficial effect of simvastatin might be mediated by the effect of anti-inflammatory action through a reduction of NF-kappaB activation, and IL-1beta and TGF-beta expression.
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Affiliation(s)
- Wei Zhang
- grid.203458.80000000086530555Department of Nephroimmunology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Qiu Li
- grid.203458.80000000086530555Department of Nephroimmunology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China ,grid.203458.80000000086530555Centre for Lipid Research, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Lijia Wang
- grid.203458.80000000086530555Department of Nephroimmunology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiqiang Yang
- grid.203458.80000000086530555Department of Nephroimmunology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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Griffin KA, Abu-Naser M, Abu-Amarah I, Picken M, Williamson GA, Bidani AK. Dynamic blood pressure load and nephropathy in the ZSF1 (fa/facp) model of type 2 diabetes. Am J Physiol Renal Physiol 2007; 293:F1605-13. [PMID: 17728379 DOI: 10.1152/ajprenal.00511.2006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Diabetes and increased blood pressure (BP) are believed to interact synergistically in the pathogenesis and progression of diabetic nephropathy. The present studies were performed to examine if there were differences in BP load and/or protective renal autoregulatory capacity between the obese diabetic Zucker fatty /spontaneously hypertensive heart failure F1 hybrid (ZSF1) ( fa/ facp) rats and their lean controls. By ∼26 wk of age, ZSF1 ( n = 13) but not their lean controls ( n = 16) had developed substantial proteinuria (180 ± 19 vs. 16 ± 1.4 mg/24 h) and glomerulosclerosis (19 ± 2.4 vs. 0.6 ± 0.2%; P < 0.001). However, average ambient systolic BP by radiotelemetry (12–26 wk of age) was modestly lower in ZSF1 than in lean controls (130 ± 1.4 vs. 137 ± 1.7 mmHg, P < 0.002), although the 24-h BP power spectra showed a mild increase at frequencies <0.1 Hz in the ZSF1. Autoregulatory capacity under anesthesia in response to step changes in perfusion pressure between 100 and 140 mmHg was similarly well preserved in both ZSF1 and lean controls at 16–18 wk of age [autoregulatory indexes (AI) <0.1]. Similarly, differences were not observed for dynamic autoregulation in conscious rats [transfer functions between BP (input) and renal blood flow (output) using chronic Transonic flow probes]. Collectively, these data indicate that the pathogenesis of nephropathy in the ZSF1 model of type 2 diabetic nephropathy is largely independent of differences in systemic BP and/or its potential renal transmission. However, these data do not exclude the possibility that the diabetic milieu may alter the glomerular capillaries in the ZSF1, such that there is an enhanced local susceptibility to injury with even normal glomerular pressures.
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Affiliation(s)
- Karen A Griffin
- Department of Internal Medicine, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153, USA.
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Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B. Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction. J Pharmacol Exp Ther 2007; 323:85-93. [PMID: 17636006 DOI: 10.1124/jpet.107.123638] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative, and inflammatory reactions that are, in part, driven by local AT1 receptor (AT1r) activation by angiotensin II (Ang II). Here we explored the effects of 5/6 nephrectomy with and without AT1r blockade (losartan for 8 weeks) on AT1r and AT2r and Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, nuclear factor kappaB (NFkappaB), 12-lipooxygenase, cyclooxygenase (COX)-1, COX-2, monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor (PAI)-1, renal T cell, and macrophage infiltration] as well as renal function and structure. The untreated group exhibited hypertension, deterioration of renal function and structure, reduced or unchanged plasma renin activity, aldosterone concentration, marked up-regulations of AT1r (250%), Ang II-expressing cell count (>20-fold), NAD(P)H oxidase subunits (gp91(phox,) p22(phox), and P47(phox); 20-40%), COX-2 (250%), 12-lipooxygenase (100%), MCP-1 (400%), and PAI-1 (>20-fold), activation of NFkappaB, and interstitial infiltrations of T cells and macrophages in the remnant kidneys. AT1r blockade attenuated the biochemical and histological abnormalities, prevented hypertension, and decelerated deterioration of renal function and structure. Thus, the study demonstrated a link between up-regulation of Ang II/AT1r system and oxidative stress, inflammation, hypertension, and progression of renal disease in rats with renal mass reduction.
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Affiliation(s)
- N D Vaziri
- Division of Nephrology and Hypertension, University of California, Irvine, CA, USA.
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Abstract
1. Macrophage accumulation is a feature of Type 2 diabetes and is associated with the development of diabetic complications (nephropathy, atherosclerosis, neuropathy and retinopathy). The present article reviews the current evidence that macrophages contribute to the complications of Type 2 diabetes. 2. Macrophage-depletion studies in rodent models have demonstrated a causal role for macrophages in the development of diabetic complications. 3. Components of the diabetic milieu (high glucose, advanced glycation end-products and oxidized low-density lipoprotein) promote macrophage accumulation (via induction of chemokines and adhesion molecules) and macrophage activation within diabetic tissues. 4. Macrophages mediate diabetic injury through a variety of mechanisms, including production of reactive oxygen species, cytokines and proteases, which result in tissue damage leading to sclerosis. 5. A number of existing and experimental therapies can indirectly reduce macrophage-mediated injury in diabetic complications. The present article discusses the use of these therapies, given alone and in combination, in suppressing macrophage accumulation and activity. 6. In conclusion, current evidence supports a critical role for macrophages in the evolution of diabetic complications. Present therapies are limited in slowing the progression of macrophage-mediated injury. Novel strategies that are more specific at targeting macrophages may provide better protection against the development of Type 2 diabetic complications.
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Affiliation(s)
- G H Tesch
- Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
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Kim CH, Vaziri ND, Rodriguez-Iturbe B. Integrin expression and H2O2 production in circulating and splenic leukocytes of obese rats. Obesity (Silver Spring) 2007; 15:2209-16. [PMID: 17890488 DOI: 10.1038/oby.2007.262] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Obesity is associated with oxidative stress and inflammation. We hypothesized that the pro-inflammatory state in obesity may result in spontaneous activation and, hence, increased generation of reactive oxygen species (ROS) and integrin expression in the circulating leukocytes. METHODS Flow cytometry was used to determine integrin expression (immunostaining) as well as superoxide and hydrogen peroxide productions (fluorescent probes) in the peripheral blood and splenic leukocyte of 24-week-old male obese normotensive and not-as-yet diabetic Zucker rats (n = 6) and their lean counterparts (n = 6). RESULTS Obese rats had hyperlipidemia and normal arterial pressure, plasma glucose, and creatinine concentrations. Nevertheless, obese rats exhibited increased hydrogen peroxide production by circulating and splenic CD4+ and CD8+ T lymphocytes and by splenic macrophages. This was accompanied by up-regulations of CD11a expression in the peripheral blood and splenic CD4+ T cells, CD11b in circulating macrophages, and CD11a and CD18 in circulating granulocytes. CONCLUSION The study revealed direct evidence of spontaneous leukocyte activation and increased ROS generation by T lymphocytes and monocytes in the peripheral blood of obese Zucker rats before the development of diabetes or hypertension. These findings illustrate the link between obesity, oxidative stress, and inflammation.
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Affiliation(s)
- Choong H Kim
- Renal Service, Hospital Universitario, Avenida Goajira s/n, Maracaibo, Venezuela
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Dominguez J, Wu P, Packer CS, Temm C, Kelly KJ. Lipotoxic and inflammatory phenotypes in rats with uncontrolled metabolic syndrome and nephropathy. Am J Physiol Renal Physiol 2007; 293:F670-9. [PMID: 17596532 DOI: 10.1152/ajprenal.00021.2007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Anomalous inflammatory responses triggered by the metabolic syndrome cause renal injury. This discovery links renal lipid accumulation with lipotoxicity to inflammation and may explain the insidious fibrosis and cellular decay characteristic of nephropathy in the metabolic syndrome. However, it is not clear whether control of inflammation protects the kidney independently of lipid accumulation, which is a required step for lipotoxicity in hyperglycemia and dyslipidemia. We hypothesized that in rats with the metabolic syndrome, and overt nephropathy, treatment with mycophenolate mofetil (MMF; 10 mg.kg(-1).day(-1) ip for 14 wk) would reduce the abnormal renal lipid depots and limit renal inflammation and injury. We studied groups of lean and obese F1 hybrid Zucker fatty diabetic/spontaneous hypertensive heart failure (ZS) rats. MMF did not affect lean rats. In obese ZS rats, MMF did not change severe hyperglycemia or the higher kidney loads of unutilized lipid and peroxidation products. Nonetheless, MMF dramatically reduced diabetes/obesity-derived systemic and renal inflammation, limited renal size, hyperfiltration, and fibrosis. These data indicate that in rats, anti-inflammatory therapy presumably acting downstream, and independently of lipotoxicity, can effectively limit renal injury and fibrosis.
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Affiliation(s)
- Jesus Dominguez
- Departments of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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Tian N, Gu JW, Jordan S, Rose RA, Hughson MD, Manning RD. Immune suppression prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 2007; 292:H1018-25. [PMID: 17040973 DOI: 10.1152/ajpheart.00487.2006] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-κB activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na + MMF (20 mg·kg−1·day−1), 0.3% Na, or 0.3% Na + MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-κB in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-κB was 41% lower in 8% Na + MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 ± 5 mmHg, and MMF reduced this arterial pressure to 124 ± 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-κB and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension.
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Affiliation(s)
- N Tian
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
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