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Chen X, Wang M, Yan Z. Recent advances in understanding the mechanisms by which sodium-glucose co-transporter type 2 inhibitors protect podocytes in diabetic nephropathy. Diabetol Metab Syndr 2025; 17:84. [PMID: 40051002 PMCID: PMC11887226 DOI: 10.1186/s13098-025-01655-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/01/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Diabetes mellitus is associated with systemic damage across multiple organ systems, and an increasing number of patients are presenting with diabetic kidney disease as its initial manifestation. The onset and progression of diabetic nephropathy is closely associated with podocyte injury. MAIN BODY Sodium-glucose cotransporter type 2 (SGLT2) inhibitors, which can significantly reduce glucose levels as well as protecting against kidney damage, are therefore widely used for the clinical treatment of patients with diabetic kidney disease. An increasing body of research has revealed that the renal protective effect of SGLT2 inhibitors is primarily derived from their enhancement of podocyte autophagy and their inhibition of inflammation and podocyte apoptosis. Multiple signaling pathways are involved in these processes. CONCLUSION A deeper exploration of the renal protective effects of SGLT2 inhibitors and the underlying mechanisms will provide more solid theoretical support for their application in the prevention and treatment of diabetic kidney disease.
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Affiliation(s)
- Xinqi Chen
- Department of Endocrinology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Mingjie Wang
- Department of Endocrinology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Zhaoli Yan
- Department of Endocrinology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China.
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Murakami A, Gotoda H, Nakamoto T, Matsuki T, Saito Y, Morikawa T, Lee S, Mima A. A Case of Myeloperoxidase Antineutrophil Cytoplasmic Antibody (MPO-ANCA)-Positive Membranoproliferative Glomerulonephritis With Latent Tuberculosis Infection. Cureus 2024; 16:e72063. [PMID: 39569301 PMCID: PMC11578663 DOI: 10.7759/cureus.72063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2024] [Indexed: 11/22/2024] Open
Abstract
Membranous proliferative glomerulonephritis (MPGN), also known as mesangiocapillary glomerulonephritis, is a relatively rare glomerulonephritis with characteristic pathology. We report the case of a 77-year-old man who presented with mild proteinuria and hematuria. Laboratory tests revealed increases in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) titers (15.9 U/mL), negative reaction for antinuclear antibodies, hematuria, and proteinuria (3.33 g/day). The patient was a carrier of Mycobacterium tuberculosis with positive results in the enzyme-linked immunosorbent assay, but negative in the sputum examination. Renal biopsy revealed double contours of the glomerular basement membrane, granular deposits of immunoglobulin (Ig) G and C3 along the capillary wall, mesangial areas, and high electron density deposits in the endothelium and subepithelium, leading to the diagnosis of MPGN type 3. The patient achieved remission only with sodium-glucose cotransporter-2 (SGLT2) inhibitor without immunosuppressive drugs. Secondary MPGN can be associated with various diseases, but the relationship between elevated MPO-ANCA levels and latent tuberculosis infection remains unclear. Consequently, there have been few reports of MPO-ANCA-positive MPGN in the context of latent tuberculosis infection. Our case report suggests a possible pattern of MPO-ANCA-positive MPGN linked to latent tuberculosis.
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Affiliation(s)
- Ami Murakami
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Hidemasa Gotoda
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Takahiro Nakamoto
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Tatsumasa Matsuki
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Yuta Saito
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Takaaki Morikawa
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Shinji Lee
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Akira Mima
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
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Mangoura SA, Ahmed MA, Zaka AZ. New Insights into the Pleiotropic Actions of Dipeptidyl Peptidase-4 Inhibitors Beyond Glycaemic Control. TOUCHREVIEWS IN ENDOCRINOLOGY 2024; 20:19-29. [PMID: 39526061 PMCID: PMC11548370 DOI: 10.17925/ee.2024.20.2.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/23/2024] [Indexed: 11/16/2024]
Abstract
Dipeptidyl peptidase-4 (DPP-4) is a multifunctional serine ectopeptidase that cleaves and modifies a plethora of substrates, including regulatory peptides, cytokines and chemokines. DPP-4 is implicated in the regulation of immune response, viral entry, cellular adhesion, metastasis and chemotaxis. Regarding its numerous substrates and extensive expression inside the body, multitasking DPP-4 has been assumed to participate in different pathophysiological mechanisms. DPP-4 inhibitors or gliptins are increasingly used for the treatment of type 2 diabetes mellitus. Several reports from experimental and clinical studies have clarified that DPP-4 inhibitors exert many beneficial pleiotropic effects beyond glycaemic control, which are mediated by anti-inflammatory, anti-oxidant, anti-fibrotic and anti-apoptotic actions. The present review will highlight the most recent findings in the literature about these pleiotropic effects and the potential mechanisms underlying these benefits, with a specific focus on the potential effectiveness of DPP-4 inhibitors in coronavirus disease-19 and diabetic kidney disease.
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Affiliation(s)
- Safwat A Mangoura
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo, Egypt
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Marwa A Ahmed
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Andrew Z Zaka
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
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Wang D, Li Y, Li G, Liu M, Zhou Z, Wu M, Song S, Bian Y, Dong J, Li X, Du Y, Zhang T, Shi Y. Inhibition of PKC-δ retards kidney fibrosis via inhibiting cGAS-STING signaling pathway in mice. Cell Death Discov 2024; 10:314. [PMID: 38972937 PMCID: PMC11228024 DOI: 10.1038/s41420-024-02087-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 06/17/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024] Open
Abstract
Kidney fibrosis is considered to be the ultimate aggregation pathway of chronic kidney disease (CKD), but its underlying mechanism remains elusive. Protein kinase C-delta (PKC-δ) plays critical roles in the control of growth, differentiation, and apoptosis. In this study, we found that PKC-δ was highly upregulated in human biopsy samples and mouse kidneys with fibrosis. Rottlerin, a PKC-δ inhibitor, alleviated unilateral ureteral ligation (UUO)-induced kidney fibrosis, inflammation, VDAC1 expression, and cGAS-STING signaling pathway activation. Adeno-associated virus 9 (AAV9)-mediated VDAC1 silencing or VBIT-12, a VDAC1 inhibitor, attenuated renal injury, inflammation, and activation of cGAS-STING signaling pathway in UUO mouse model. Genetic and pharmacologic inhibition of STING relieved renal fibrosis and inflammation in UUO mice. In vitro, hypoxia resulted in PKC-δ phosphorylation, VDAC1 oligomerization, and activation of cGAS-STING signaling pathway in HK-2 cells. Inhibition of PKC-δ, VDAC1 or STING alleviated hypoxia-induced fibrotic and inflammatory responses in HK-2 cells, respectively. Mechanistically, PKC-δ activation induced mitochondrial membrane VDAC1 oligomerization via direct binding VDAC1, followed by the mitochondrial DNA (mtDNA) release into the cytoplasm, and subsequent activated cGAS-STING signaling pathway, which contributed to the inflammation leading to fibrosis. In conclusion, this study has indicated for the first time that PKC-δ is an important regulator in kidney fibrosis by promoting cGAS-STING signaling pathway which mediated by VDAC1. PKC-δ may be useful for treating renal fibrosis and subsequent CKD.
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Affiliation(s)
- Dongyun Wang
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Yue Li
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Guiying Li
- Department of Nephrology, Affiliated Hospital of Hebei University of Engineering, Handan, 056000, China
| | - Mengyu Liu
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Zihui Zhou
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Ming Wu
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Shan Song
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Yawei Bian
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Jiajia Dong
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Xinran Li
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Yunxia Du
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
| | - Tao Zhang
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China
- Department of Nephrology, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Yonghong Shi
- Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China.
- Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China.
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Qin P, Zhou P, Huang Y, Long B, Gao R, Zhang S, Zhu B, Li YQ, Li Q. Upregulation of rate-limiting enzymes in cholesterol metabolism by PKCδ mediates endothelial apoptosis in diabetic wound healing. Cell Death Discov 2024; 10:263. [PMID: 38811564 PMCID: PMC11137154 DOI: 10.1038/s41420-024-02030-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 05/03/2024] [Accepted: 05/14/2024] [Indexed: 05/31/2024] Open
Abstract
Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by heightened endothelial apoptosis and impaired angiogenesis. In this study, we aimed to investigate the role of protein kinase Cδ (PKCδ) in regulating endothelial apoptosis in diabetic wounds by promoting cholesterol biosynthesis. The expression of PKCδ was increased in human umbilical vascular endothelial cells (HUVECs) cultivated in high glucose medium and skin tissue isolated from diabetic mice. High glucose-induced HUVECs apoptosis was reduced by PKCδ inhibition with siRNA or rottlerin. RNA-seq identified two enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), as the downstream of PKCδ. PKCδ knockdown or inhibition suppressed the expression of HMGCS1 and HMGCR and lowered free cholesterol (FC) levels. Cholesterol restored high glucose-induced apoptosis in siRNA- or rottlerin-treated HUVECs. In vivo use of rosuvastatin calcium, an inhibitor of HMGCR, downregulated free cholesterol levels and accelerated the wound healing process. In conclusion, PKCδ expression in endothelial cells was activated by high glucose, which subsequently upregulates the expression of two enzymes catalyzing cholesterol biosynthesis, HMGCS1 and HMGCR. Enhanced cholesterol biosynthesis raises free cholesterol levels, promotes endothelial apoptosis, and finally delays wound healing.
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Affiliation(s)
- Peiliang Qin
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng Zhou
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yating Huang
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Binbin Long
- General Surgery Department, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan, Hubei, China
| | - Ruikang Gao
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shan Zhang
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bingjie Zhu
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yi-Qing Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Qin Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Tang Y, Liu T, Sun S, Peng Y, Huang X, Wang S, Zhou Z. Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease. J Inflamm Res 2024; 17:2861-2871. [PMID: 38741613 PMCID: PMC11090192 DOI: 10.2147/jir.s451398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 04/25/2024] [Indexed: 05/16/2024] Open
Abstract
GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these factors regulating GDF-15 is still unclear and more research is needed to explore them. GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. In addition, the role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. However, the specific mechanism of these pathways remains unclear. Accordingly, more research on the specific mechanism of GDF-15 affecting kidney disease is needed in the future. In conclusion, GDF-15 may be a therapeutic target for kidney disease.
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Affiliation(s)
- Yifang Tang
- Department of Nephrology, the First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
| | - Tao Liu
- Organ Transplantation Center, the First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
| | - Shibo Sun
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
| | - Youbo Peng
- Department of Nephrology, the First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
| | - Xiaoxiao Huang
- Department of Nephrology, Xishuangbanna Dai Autonomous Prefecture People’s Hospital, Xishuangbanna, People’s Republic of China
| | - Shuangquan Wang
- Department of Nephrology, Xishuangbanna Dai Autonomous Prefecture People’s Hospital, Xishuangbanna, People’s Republic of China
| | - Zhu Zhou
- Department of Nephrology, the First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
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Yu MG, Gordin D, Fu J, Park K, Li Q, King GL. Protective Factors and the Pathogenesis of Complications in Diabetes. Endocr Rev 2024; 45:227-252. [PMID: 37638875 PMCID: PMC10911956 DOI: 10.1210/endrev/bnad030] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/13/2023] [Accepted: 08/24/2023] [Indexed: 08/29/2023]
Abstract
Chronic complications of diabetes are due to myriad disorders of numerous metabolic pathways that are responsible for most of the morbidity and mortality associated with the disease. Traditionally, diabetes complications are divided into those of microvascular and macrovascular origin. We suggest revising this antiquated classification into diabetes complications of vascular, parenchymal, and hybrid (both vascular and parenchymal) tissue origin, since the profile of diabetes complications ranges from those involving only vascular tissues to those involving mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding the pathogenesis of diabetes complications, in which the focus has shifted from studies on risks to those on the interplay between risk and protective factors. While risk factors are clearly important for the development of chronic complications in diabetes, recent studies have established that protective factors are equally significant in modulating the development and severity of diabetes complications. These protective responses may help explain the differential severity of complications, and even the lack of pathologies, in some tissues. Nevertheless, despite the growing number of studies on this field, comprehensive reviews on protective factors and their mechanisms of action are not available. This review thus focused on the clinical, biochemical, and molecular mechanisms that support the idea of endogenous protective factors, and their roles in the initiation and progression of chronic complications in diabetes. In addition, this review also aimed to identify the main needs of this field for future studies.
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Affiliation(s)
- Marc Gregory Yu
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Daniel Gordin
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
- Department of Nephrology, University of Helsinki and Helsinki University Central Hospital, Stenbäckinkatu 9, FI-00029 Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Tukholmankatu 8, 00290 Helsinki, Finland
| | - Jialin Fu
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Kyoungmin Park
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Qian Li
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - George Liang King
- Research Division, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
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Mima A, Gotoda H, Lee S. Safety and Efficacy of Dotinurad on Uric Acid in Patients With Chronic Kidney Disease With Estimated Glomerular Filtration Rate Below 25 mL/Min/1.73 m². Cureus 2024; 16:e57362. [PMID: 38694413 PMCID: PMC11061547 DOI: 10.7759/cureus.57362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2024] [Indexed: 05/04/2024] Open
Abstract
Introduction Dotinurad is being developed as a selective uric acid reabsorption inhibitor. However, its effect on lowering serum uric acid (UA) levels in chronic kidney disease (CKD) patients with severe renal dysfunction is unknown. Therefore, the purpose of this study was to determine the effect of dotinurad on renal function in CKD patients with an estimated glomerular filtration rate (eGFR) below 25 mL/min/1.73 m2. Methods Seven patients with CKD who received dotinurad 0.5 mg to 4 mg per day were studied retrospectively. Changes in UA, eGFR, and urine protein-to-creatinine ratio (UPCR) were analyzed. The observation period was 10.9±2.1 months. Results Serum UA levels were decreased and maintained with dotinurad administration. Nevertheless, there were no improvements noted in renal function. Additionally, no serious adverse effects were identified in any of the patients throughout the observation period. Conclusion Although the sample size in this study was small, our findings demonstrate the efficacy of dotinurad in individuals with advanced CKD who have an eGFR lower than 25 mL/min/1.73 m2.
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Affiliation(s)
- Akira Mima
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Hidemasa Gotoda
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
| | - Shinji Lee
- Nephrology, Osaka Medical and Pharmaceutical University, Takatsuki, JPN
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Sinha SK, Nicholas SB. Pathomechanisms of Diabetic Kidney Disease. J Clin Med 2023; 12:7349. [PMID: 38068400 PMCID: PMC10707303 DOI: 10.3390/jcm12237349] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 03/15/2024] Open
Abstract
The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. Within each pathway, several mediators contribute to the development of renal structural and functional changes. Some of these mediators, such as inflammatory cytokines, reactive oxygen species, and transforming growth factor β are shared among the different pathways, leading to significant overlap and interaction between them. While current treatment options for DKD have shown advancement over previous strategies, their effectiveness remains somewhat constrained as patients still experience residual risk of disease progression. Therefore, a comprehensive grasp of the molecular mechanisms underlying the onset and progression of DKD is imperative for the continued creation of novel and groundbreaking therapies for this condition. In this review, we discuss the current achievements in fundamental research, with a particular emphasis on individual factors and recent developments in DKD treatment.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- College of Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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Qin P, He C, Ye P, Li Q, Cai C, Li Y. PKCδ regulates the vascular biology in diabetic atherosclerosis. Cell Commun Signal 2023; 21:330. [PMID: 37974282 PMCID: PMC10652453 DOI: 10.1186/s12964-023-01361-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 10/20/2023] [Indexed: 11/19/2023] Open
Abstract
Diabetes mellitus, known for its complications, especially vascular complications, is becoming a globally serious social problem. Atherosclerosis has been recognized as a common vascular complication mechanism in diabetes. The diacylglycerol (DAG)-protein kinase C (PKC) pathway plays an important role in atherosclerosis. PKCs can be divided into three subgroups: conventional PKCs (cPKCs), novel PKCs (nPKCs), and atypical PKCs (aPKCs). The aim of this review is to provide a comprehensive overview of the role of the PKCδ pathway, an isoform of nPKC, in regulating the function of endothelial cells, vascular smooth muscle cells, and macrophages in diabetic atherosclerosis. In addition, potential therapeutic targets regarding the PKCδ pathway are summarized. Video Abstract.
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Affiliation(s)
- Peiliang Qin
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Changhuai He
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pin Ye
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chuanqi Cai
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Yiqing Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Jiang W, Gan C, Zhou X, Yang Q, Chen D, Xiao H, Dai L, Chen Y, Wang M, Yang H, Li Q. Klotho inhibits renal ox-LDL deposition via IGF-1R/RAC1/OLR1 signaling to ameliorate podocyte injury in diabetic kidney disease. Cardiovasc Diabetol 2023; 22:293. [PMID: 37891556 PMCID: PMC10612302 DOI: 10.1186/s12933-023-02025-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
OBJECTIVE Diabetic kidney disease (DKD) is characterized by the abnormal deposition of oxidized low-density lipoprotein (ox-LDL), which contributes to podocyte damage. Klotho, an aging suppressor that plays a critical role in protecting podocytes in DKD, is mainly expressed in kidney tubular epithelium and secreted in the blood. However, it has not been established whether Klotho can alleviate podocyte injury by inhibiting renal ox-LDL deposition, and the potential molecular mechanisms require further investigation. METHODS We conducted a comprehensive analysis of serum and kidney biopsy samples obtained from patients diagnosed with DKD. Additionally, to explore the underlying mechanism of Klotho in the deposition of ox-LDL in the kidneys, we employed a mouse model of DKD with the Klotho genotype induced by streptozotocin (STZ). Furthermore, we conducted meticulous in vitro experiments on podocytes to gain further insights into the specific role of Klotho in the deposition of ox-LDL within the kidney. RESULTS Our groundbreaking study unveiled the remarkable ability of the soluble form of Klotho to effectively inhibit high glucose-induced ox-LDL deposition in podocytes affected by DKD. Subsequent investigations elucidated that Klotho achieved this inhibition by reducing the expression of the insulin/insulin-like growth factor 1 receptor (IGF-1R), consequently leading to a decrease in the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) and an enhancement of mitochondrial function. Ultimately, this series of events culminated in a significant reduction in the expression of the oxidized low-density lipoprotein receptor (OLR1), thereby resulting in a notable decrease in renal ox-LDL deposition in DKD. CONCLUSION Our findings suggested that Klotho had the potential to mitigate podocyte injury and reduced high glucose-induced ox-LDL deposition in glomerulus by modulating the IGF-1R/RAC1/OLR1 signaling. These results provided valuable insights that could inform the development of novel strategies for diagnosing and treating DKD.
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Affiliation(s)
- Wei Jiang
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Chun Gan
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xindi Zhou
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Qing Yang
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Dan Chen
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Han Xiao
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Lujun Dai
- Department of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Yaxi Chen
- Department of Infectious Diseases, Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Mo Wang
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Haiping Yang
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
| | - Qiu Li
- Chongqing Key Laboratory of Pediatrics, Department of Nephrology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
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12
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Lizotte F, Rousseau M, Denhez B, Lévesque D, Guay A, Liu H, Moreau J, Higgins S, Sabbagh R, Susztak K, Boisvert FM, Côté AM, Geraldes P. Deletion of protein tyrosine phosphatase SHP-1 restores SUMOylation of podocin and reverses the progression of diabetic kidney disease. Kidney Int 2023; 104:787-802. [PMID: 37507049 DOI: 10.1016/j.kint.2023.06.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/03/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023]
Abstract
Both clinical and experimental data suggest that podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD). Although the mechanisms underlying the development of podocyte loss are not completely understood, critical structural proteins such as podocin play a major role in podocyte survival and function. We have reported that the protein tyrosine phosphatase SHP-1 expression increased in podocytes of diabetic mice and glomeruli of patients with diabetes. However, the in vivo contribution of SHP-1 in podocytes is unknown. Conditional podocyte-specific SHP-1-deficient mice (Podo-SHP-1-/-) were generated to evaluate the impact of SHP-1 deletion at four weeks of age (early) prior to the onset of diabetes and after 20 weeks (late) of diabetes (DM; Ins2+/C96Y) on kidney function (albuminuria and glomerular filtration rate) and kidney pathology. Ablation of the SHP-1 gene specifically in podocytes prevented and even reversed the elevated albumin/creatinine ratio, glomerular filtration rate progression, mesangial cell expansion, glomerular hypertrophy, glomerular basement membrane thickening and podocyte foot process effacement induced by diabetes. Moreover, podocyte-specific deletion of SHP-1 at an early and late stage prevented diabetes-induced expression of collagen IV, fibronectin, transforming growth factor-β, transforming protein RhoA, and serine/threonine kinase ROCK1, whereas it restored nephrin, podocin and cation channel TRPC6 expression. Mass spectrometry analysis revealed that SHP-1 reduced SUMO2 post-translational modification of podocin while podocyte-specific deletion of SHP-1 preserved slit diaphragm protein complexes in the diabetic context. Thus, our data uncovered a new role of SHP-1 in the regulation of cytoskeleton dynamics and slit diaphragm protein expression/stability, and its inhibition preserved podocyte function preventing DKD progression.
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Affiliation(s)
- Farah Lizotte
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Marina Rousseau
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Benoit Denhez
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Dominique Lévesque
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Andréanne Guay
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - HongBo Liu
- Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Julie Moreau
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Sarah Higgins
- Division of Nephrology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Robert Sabbagh
- Department of Surgery, Université de Sherbrooke, Québec, Canada
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Anne Marie Côté
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada; Division of Nephrology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Pedro Geraldes
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada; Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
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13
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Tong M, Gu C, Yu Q, Ma J. Serum JKAP reflects Th2 and Th17 cell levels, and diabetic nephropathy risk and severity in diabetes mellitus patients. Biomark Med 2023; 17:701-710. [PMID: 38179996 DOI: 10.2217/bmm-2023-0422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2024] Open
Abstract
Objective: This study aimed to explore the potency of serum JKAP for estimating diabetic nephropathy risk in diabetes mellitus (DM) patients. Methods: Serum JKAP was detected in 212 DM patients. According to urinary albumin-to-creatinine ratio, DM patients were divided into normoalbuminuria, microalbuminuria and macroalbuminuria groups. Results: JKAP declined in the macroalbuminuria group versus normoalbuminuria group (p < 0.001). In DM patients, JKAP inversely correlated with Th17 cells (p < 0.001) but positively related to Th2 cells (p = 0.003). After adjustment, JKAP independently estimated lower risks of albuminuria (microalbuminuria + macroalbuminuria; odds ratio = 0.966, p < 0.001) and macroalbuminuria (odds ratio = 0.948; p = 0.002). Conclusion: Serum JKAP reflects increased Th2 cells, decreased Th17 cells, and lower diabetic nephropathy risk and severity in DM patients.
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Affiliation(s)
- Meili Tong
- Department of Internal Medicine, Harbin Traditional Chinese Medicine Hospital, Harbin, 150070, China
| | - Changrui Gu
- Department of Endocrinology, Heilongjiang Ruijing Diabetes Hospital, Harbin, 150096, China
| | - Qiuzhi Yu
- Department of Endocrinology, Heilongjiang Ruijing Diabetes Hospital, Harbin, 150096, China
| | - Jian Ma
- Department of Endocrinology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
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14
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Mima A, Lee R, Murakami A, Gotoda H, Akai R, Kidooka S, Nakamoto T, Kido S, Lee S. Effect of finerenone on diabetic kidney disease outcomes with estimated glomerular filtration rate below 25 mL/min/1.73 m 2. Metabol Open 2023; 19:100251. [PMID: 37497038 PMCID: PMC10366575 DOI: 10.1016/j.metop.2023.100251] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 07/28/2023] Open
Abstract
Background In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease trial, finerenone reduced the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes, while in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial, it improved renal and cardiovascular outcomes in patients with advanced CKD. However, no previous studies have assessed patients with CKD and type 2 diabetes with an estimated glomerular filtration rate (eGFR) below 25 mL/min/1.73 m2. Methods Nine patients with CKD and type 2 diabetes who received finerenone 10 mg/day were analyzed retrospectively. Changes in eGFR, urinary protein, and serum potassium levels were studied from 1 year before administration of finerenone until 6 months after administration. Results The mean baseline eGFR slope was -7.63 ± 9.84 (mL/min/1.73 m2/year). After finerenone treatment, the mean eGFR slope significantly improved -1.44 ± 3.17 (mL/min/1.73 m2/6 months, P=0.038). However, finerenone treatment did not significantly reduce proteinuria. Furthermore, finerenone did not increase serum potassium levels. Conclusions Patients treated with finerenone showed a significantly slower decline in eGFR. Furthermore, aside from the present study, no reports have indicated the effectiveness of finerenone in patients with advanced CKD with an eGFR below 25 mL/min/1.73 m2. As confirmed in our clinical trials, the finding that finerenone is effective in a wide range of renal functions can be generalized to clinical practice. However, sample size in this study was small. Thus, further large-scale investigations will be needed.
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Affiliation(s)
- Akira Mima
- Corresponding author. Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, 569-8686, Japan.
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15
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Mima A, Murakami A, Lee R, Lee S. Predictive significance of glomerular insulin receptor substrate-1 in patients with diabetic kidney disease. Metabol Open 2023; 18:100240. [PMID: 37025096 PMCID: PMC10070893 DOI: 10.1016/j.metop.2023.100240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Background In rodents, glomerular expression of insulin receptor substrate 1 (IRS1) is decreased in diabetic kidney disease (DKD) and reduced associated functioning is involved in the development and progression of DKD. This study aimed to evaluate the significance of glomerular IRS1 expression in DKD patients, and investigated whether glomerular IRS1 expression can reflect renal pathology and predict renal outcomes. Methods This study included 10 patients who underwent renal biopsy and were diagnosed with DKD or minor glomerular abnormality (MGA). IRS1-positive cells were determined based on renal biopsy and immunostaining, and the associations of the number of these cells with baseline and prognostic parameters were analyzed. Results IRS1-positive cells were significantly decreased in DKD than in MGA. IRS1 positivity tended to be negatively correlated with global glomerulosclerosis and tubulointerstitial fibrosis. The rate of change in estimated glomerular filtration rate before and 12 months after renal biopsy was positively correlated to the number of IRS1-positive cells. Furthermore, a tendency towards negative correlation was observed between the number of glomerular IRS1-positive cells and the proteinuria. Conclusions This study shows the glomerular IRS1-positive cell count was significantly decreased in DKD, and that the degree IRS1 positivity was partially correlated with renal pathology and function.
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16
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Mima A, Yasuzawa T. Role of insulin signaling and its associated signaling in glomerulus for diabetic kidney disease. Histol Histopathol 2023; 38:487-492. [PMID: 36326211 DOI: 10.14670/hh-18-543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
The number of patients with diabetic kidney disease (DKD) has been rising significantly over the last several decades and is one of the most frequent causes of chronic kidney disease (CKD) in the United States. Hyperglycemia accelerates development of DKD, a direct result of increased intracellular glucose availability. Two large clinical studies, the Diabetes Control and Complications Trial in type 1 diabetes and the United Kingdom Prospective Diabetes Study in type 2 diabetes showed that intensive glycemic control delayed the onset and the progression of DKD. On the other hand, it is reported that glycemic control alone is not sufficient to control DKD progression. Recent data support that insulin signaling and its associated signaling contribute significantly to preserve glomerular function. However, little is known about the key regulators of insulin signaling in glomerular component cells. In this review, we summarize the novel knowledge regarding the reno-protective effects of insulin signaling or its associated signaling in glomerular constituent cells on DKD.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
| | - Toshinori Yasuzawa
- Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, Japan
- School of Human Cultures, University of Shiga Prefecture, Shiga, Japan
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17
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Mima A. Enarodustat Treatment for Renal Anemia in Patients With Non-dialysis Chronic Kidney Disease. In Vivo 2023; 37:825-829. [PMID: 36881056 PMCID: PMC10026677 DOI: 10.21873/invivo.13148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 12/30/2022] [Accepted: 01/11/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND/AIM Renal anemia is a major complication in patients with chronic kidney disease (CKD), leading to morbidity and mortality. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHI), also called HIF stabilizers, increase endogenous erythropoietin production and are expected to be novel orally administrated agents for renal anemia in CKD. Enarodustat is being developed as an oral HIF-PHI. It was recently approved in Japan and clinical development is ongoing in the USA and South Korea. Therefore, there are only a few real-world data regarding treatment of renal anemia using enarodustat. This study evaluated the efficacy of enarodustat in patients with non-dialysis CKD. PATIENTS AND METHODS Nine patients (78±11 years old, male=6, female=3) were enrolled in this study. Patients received enarodustat as first-line therapy or changed from erythropoiesis stimulating agents (2-6 mg). The observation period was 4.8±2.0 months. RESULTS Levels of hemoglobin were effectively increased and maintained with enarodustat administration. C-reactive protein and serum ferritin were significantly decreased, but no change in renal function was observed. Furthermore, no serious adverse effects were recognized in all patients during the study. CONCLUSION Enarodustat is an effective and relatively well-tolerated agent for the treatment of renal anemia in patients with non-dialysis CKD.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, Japan
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18
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Imeri F, Stepanovska Tanturovska B, Manaila R, Pavenstädt H, Pfeilschifter J, Huwiler A. Loss of S1P Lyase Expression in Human Podocytes Causes a Reduction in Nephrin Expression That Involves PKCδ Activation. Int J Mol Sci 2023; 24:3267. [PMID: 36834691 PMCID: PMC9965238 DOI: 10.3390/ijms24043267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Sphingosine 1-phosphate (S1P) lyase (SPL, Sgpl1) is an ER-associated enzyme that irreversibly degrades the bioactive lipid, S1P, and thereby regulates multiple cellular functions attributed to S1P. Biallelic mutations in the human Sglp1 gene lead to a severe form of a particular steroid-resistant nephrotic syndrome, suggesting that the SPL is critically involved in maintaining the glomerular ultrafiltration barrier, which is mainly built by glomerular podocytes. In this study, we have investigated the molecular effects of SPL knockdown (kd) in human podocytes to better understand the mechanism underlying nephrotic syndrome in patients. A stable SPL-kd cell line of human podocytes was generated by the lentiviral shRNA transduction method and was characterized for reduced SPL mRNA and protein levels and increased S1P levels. This cell line was further studied for changes in those podocyte-specific proteins that are known to regulate the ultrafiltration barrier. We show here that SPL-kd leads to the downregulation of the nephrin protein and mRNA expression, as well as the Wilms tumor suppressor gene 1 (WT1), which is a key transcription factor regulating nephrin expression. Mechanistically, SPL-kd resulted in increased total cellular protein kinase C (PKC) activity, while the stable downregulation of PKCδ revealed increased nephrin expression. Furthermore, the pro-inflammatory cytokine, interleukin 6 (IL-6), also reduced WT1 and nephrin expression. In addition, IL-6 caused increased PKCδ Thr505 phosphorylation, suggesting enzyme activation. Altogether, these data demonstrate that nephrin is a critical factor downregulated by the loss of SPL, which may directly cause podocyte foot process effacement as observed in mice and humans, leading to albuminuria, a hallmark of nephrotic syndrome. Furthermore, our in vitro data suggest that PKCδ could represent a new possible pharmacological target for the treatment of a nephrotic syndrome induced by SPL mutations.
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Affiliation(s)
- Faik Imeri
- Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland
| | | | - Roxana Manaila
- Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland
| | - Hermann Pavenstädt
- Medizinische Klinik D, University Hospital Münster, D-48149 Münster, Germany
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany
| | - Andrea Huwiler
- Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland
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Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications. Antioxidants (Basel) 2023; 12:antiox12010123. [PMID: 36670985 PMCID: PMC9855127 DOI: 10.3390/antiox12010123] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/10/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The global prevalence of diabetes continues to increase partly due to rapid urbanization and an increase in the aging population. Consequently, this is associated with a parallel increase in the prevalence of diabetic vascular complications which significantly worsen the burden of diabetes. For these diabetic vascular complications, there is still an unmet need for safe and effective alternative/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic options to come from natural products such as plants. Hyperglycemia-induced oxidative stress is central to the development of diabetes and diabetic complications. Furthermore, oxidative stress-induced inflammation and insulin resistance are central to endothelial damage and the progression of diabetic complications. Human and animal studies have shown that polyphenols could reduce oxidative stress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols is attributed to their modulatory effect on endogenous antioxidant systems. This review attempts to summarize the established effects of polyphenols on endogenous antioxidant systems from the literature. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenols for diabetic vascular complications are also discussed.
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Toll-like receptors 2 and 4 stress signaling and sodium-glucose cotransporter-2 in kidney disease. Mol Cell Biochem 2022:10.1007/s11010-022-04652-5. [PMID: 36586092 DOI: 10.1007/s11010-022-04652-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023]
Abstract
Kidney disease is the 6th fastest-growing cause of death and a serious global health concern that urges effective therapeutic options. The inflammatory response is an initial reaction from immune and parenchymal cells in kidney diseases. Toll-like receptors (TLR) 2 and 4 are highly expressed by various kidney cells and respond to 'signaling danger' proteins, such as high mobility group box binding protein 1 (HMGB1) and prompt the progression of kidney disease by releasing inflammatory mediators. Burgeoning reports suggest that both SGLT2 and ER stress elevates TLR2/4 signaling via different axis. Moreover, SGLT2 signaling aggravates inflammation under the disease condition by promoting the NLR family pyrin domain-containing three inflammasomes and ER stress. Intriguingly, TLR2/4 downstream adaptors activate ER stress regulators. The above-discussed interactions imply that TLR2/4 does more than immune response during kidney disease. Here, we discuss in detail evidence of the roles and regulation of TLR2/4 in the context of a relationship between ER stress and SGLT2. Also, we highlighted different preclinical studies of SGLT2 inhibitors against TLR2/4 signaling in various kidney diseases. Moreover, we discuss the observational and interventional evidence about the relation between TLR2/4, ER stress, and SGLT2, which may represent the TLR2/4 as a potential therapeutic target for kidney disease.
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21
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Alqallaf A, Swan P, Docherty NG. Renal insulin resistance in type 2 diabetes mellitus and progression of chronic kidney disease: potential pathogenic mechanisms. Expert Rev Endocrinol Metab 2022; 17:523-532. [PMID: 36203374 DOI: 10.1080/17446651.2022.2131534] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/28/2022] [Indexed: 01/06/2023]
Abstract
INTRODUCTION A bidirectional association exists between insulin resistance (IR) and chronic kidney disease (CKD) in Type 2 Diabetes Mellitus (T2DM). Baseline measures of IR are predictive of CKD progression, and uremia in progressive CKD is itself, in turn, associated with a worsening of IR. Pre-clinical research reveals that intrinsic IR in glomerular podocytes and the renal tubule may serve as a pathogenic driver of CKD in T2DM. AREAS COVERED The present manuscript takes as its point of departure, the recently identified prognostic utility of severe insulin resistance as a predictor of CKD in T2DM. Findings from a series of studies describing the association of IR with pathological alterations in both established, and less commonly assessed dynamic measures of renal impairment are discussed. Drawing upon the pre-clinical mechanistic evidence base, the cellular and molecular basis of intrinsic renal IR as a promoter of CKD is considered. EXPERT OPINION Measurement of insulin sensitivity may add value to profiling of renal risk in T2DM. Rational selection of therapeutic strategies targeting the enhancement of insulin sensitivity merits special attention regarding the personalized management of CKD in insulin resistance predominant T2DM.
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Affiliation(s)
- Alrataj Alqallaf
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrick Swan
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Neil G Docherty
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
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22
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Lizotte F, Robillard S, Lavoie N, Rousseau M, Denhez B, Moreau J, Higgins S, Sabbagh R, Côté AM, Geraldes P. Enhanced SHP-1 Expression in Podocyturia Is Associated with Kidney Dysfunction in Patients with Diabetes. KIDNEY360 2022; 3:1710-1719. [PMID: 36514736 PMCID: PMC9717659 DOI: 10.34067/kid.0002152022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 08/25/2022] [Indexed: 01/12/2023]
Abstract
Background Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease worldwide. Despite significant advances in kidney care, there is a need to improve noninvasive techniques to predict the progression of kidney disease better for patients with diabetes. After injury, podocytes are shed in urine and may be used as a biologic tool. We previously reported that SHP-1 is upregulated in the kidney of diabetic mice, leading to podocyte dysfunction and loss. Our objective was to evaluate the expression levels of SHP-1 in urinary podocytes and kidney tissues of patients with diabetes. Methods In this prospective study, patients with and without diabetes were recruited for the quantification of SHP-1 in kidney tissues, urinary podocytes, and peripheral blood monocytes. Immunochemistry and mass spectrometry techniques were applied for kidney tissues. Urinary podocytes were counted, and expression of SHP-1 and podocyte markers were measured by quantitative PCR. Results A total of 66 participants (diabetic n=48, nondiabetic n=18) were included in the analyses. Diabetes was associated with increased SHP-1 expression in kidney tissues (P=0.03). Nephrin and podocin mRNA was not significantly increased in urinary podocytes from patients with diabetes compared with those without diabetes, whereas levels of SHP-1 mRNA expression significantly correlated with HbA1c and estimated glomerular filtration rate (eGFR). Additionally, follow-up (up to 2 years post recruitment) evaluation indicated that SHP-1 mRNA expression continued to increase with eGFR decline. Conclusions Levels of SHP-1 in urinary podocytes may serve as an additional marker of glomerular disease progression in this population.
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Affiliation(s)
- Farah Lizotte
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada
| | - Stéphanie Robillard
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada
| | - Nicolas Lavoie
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada
| | - Marina Rousseau
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada
| | - Benoit Denhez
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada
| | - Julie Moreau
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada
| | - Sarah Higgins
- Department of Medicine, Division of Nephrology, Université de Sherbrooke, Québec, Canada
| | - Robert Sabbagh
- Department of Surgery, Université de Sherbrooke, Québec, Canada
| | - Anne-Marie Côté
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada,Department of Medicine, Division of Nephrology, Université de Sherbrooke, Québec, Canada
| | - Pedro Geraldes
- Research Center, Centre Hospitalier, Université de Sherbrooke, Québec, Canada,Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Québec, Canada
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Pan D, Xu L, Guo M. The role of protein kinase C in diabetic microvascular complications. Front Endocrinol (Lausanne) 2022; 13:973058. [PMID: 36060954 PMCID: PMC9433088 DOI: 10.3389/fendo.2022.973058] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Protein kinase C (PKC) is a family of serine/threonine protein kinases, the activation of which plays an important role in the development of diabetic microvascular complications. The activation of PKC under high-glucose conditions stimulates redox reactions and leads to an accumulation of redox stress. As a result, various types of cells in the microvasculature are influenced, leading to changes in blood flow, microvascular permeability, extracellular matrix accumulation, basement thickening and angiogenesis. Structural and functional disorders further exacerbate diabetic microvascular complications. Here, we review the roles of PKC in the development of diabetic microvascular complications, presenting evidence from experiments and clinical trials.
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Affiliation(s)
- Deng Pan
- Xiyuan hospital of China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Lin Xu
- Gynecological Department of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ming Guo
- Xiyuan hospital of China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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24
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Low molecular weight fucoidan alleviates cerebrovascular damage by promoting angiogenesis in type 2 diabetes mice. Int J Biol Macromol 2022; 217:345-355. [PMID: 35841956 DOI: 10.1016/j.ijbiomac.2022.07.053] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 12/11/2022]
Abstract
Diabetes leading to brain glucose metabolism disorders and cerebrovascular complications. Fucoidan is a kind of sulfated polysaccharides which found in brown algae, has multiply bioactivities and considered to be a promising therapeutic agent. Despite the increasing amount of evidence suggesting the diabetes protective role of fucoidans, the effect of fucoidan on brain abnormalities in type 2 diabetes mellitus patients remains unclear. In this study a low molecular weight fucoidan (LMWF) was obtained from Saccharina japonica and its effect on the cerebrovascular damage in db/db mice was investigated. Results were shown after LMWF treatment, the degree of cerebrovascular damage, the number of apoptotic neuronal cells and the inflammation were all decreased in db/db mice. Moreover, LMWF could up-regulates CD34 and VEGFA expression in db/db mice brain, and the subintestinal vessel angiogenesis in zebrafish was also promoted by LMWF. Moreover, the lumen formation of HUVEC endothelial cells was rescued by LMWF which was destroyed in high glucose treated endothelial cells. Further study found, LMWF alleviates vascular injury by up-regulating the expression level of phosphorylated PI3K and phosphorylated AKT. Our study indicates that LMWF has the potential to develop a cerebrovascular protection agent for type 2 diabetes patients.
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25
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Su L, Yuan H, Zhang H, Wang R, Fu K, Yin L, Ren Y, Liu H, Fang Q, Wang J, Guo D. PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity. FEBS Open Bio 2022; 12:1761-1770. [PMID: 35748097 PMCID: PMC9527591 DOI: 10.1002/2211-5463.13459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/31/2022] [Accepted: 06/22/2022] [Indexed: 12/14/2022] Open
Abstract
Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over-proliferation of cyst-lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an adenosine monophosphate-activated protein kinase (AMPK) activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF-06409577, an AMPK activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF-06409577 effectively down-regulated mammalian target of rapamycin pathway-mediated proliferation of cyst-lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator-regulated cystic fluid secretion. Overall, our data suggest that PF-06409577 holds therapeutic potential for ADPKD treatment.
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Affiliation(s)
- Limin Su
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Haoxing Yuan
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Haoran Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Ruoqi Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Kequan Fu
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Long Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Ying Ren
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Hongli Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
| | - Qian Fang
- Department of UrologyThe Affiliated Hospital of Xuzhou Medical UniversityChina
| | - Junqi Wang
- Department of UrologyThe Affiliated Hospital of Xuzhou Medical UniversityChina
| | - Dong Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityChina
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26
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Mima A. A Narrative Review of Diabetic Kidney Disease: Previous and Current Evidence-Based Therapeutic Approaches. Adv Ther 2022; 39:3488-3500. [PMID: 35751762 DOI: 10.1007/s12325-022-02223-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/13/2022] [Indexed: 12/19/2022]
Abstract
Diabetic kidney disease (DKD) is one of the most important diabetic complications. DKD is also the most common cause of chronic kidney disease (CKD) and end-stage renal disease. This review focused on potential therapeutic drugs for which there is established evidence of treatment for DKD. The earliest evidence for DKD treatment was established with renin-angiotensin system (RAS) inhibitors; however, their efficacy was partial. Recently, the sodium-glucose co-transporter 2 (SGLT2) inhibitors, including empagliflozin (EMPA-REG Outcome), canagliflozin (CREDENCE trial), and dapagliflozin (DAPA-CKD), demonstrated a significant and clinically relevant reduction in the risks of albuminuria and progression of nephropathy, doubling of serum creatinine levels, and initiation of renal replacement therapy. Additionally, incretin-based therapeutic agents, such as glucagon-like peptide 1, liraglutide (LEADER), and dipeptidyl peptidase 4 inhibitors, linagliptin (CARMERINA) have elicited vasotropic actions, suggesting a potential for reducing the risk of DKD. Until recently, mineralocorticoid receptor antagonists (MRAs) have not been suitable for DKD treatment because of their adverse effect of hyperkalemia. In contrast, finerenone, a non-steroidal MRA, significantly reduced renal composite endpoint without severe hyperkalemia that would force its discontinuation (FIDELIO-DKD). Thus, the mainstay treatments of DKD are RAS inhibitors, SGLT2 inhibitors, incretin-based therapeutic agents, and non-steroidal MRA, or in other words, the DKD "fantastic four".
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, 569-8686, Japan.
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27
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Honzawa N, Fujimoto K, Kobayashi M, Kohno D, Kikuchi O, Yokota-Hashimoto H, Wada E, Ikeuchi Y, Tabei Y, Dorn GW, Utsunomiya K, Nishimura R, Kitamura T. Protein Kinase C (Pkc)-δ Mediates Arginine-Induced Glucagon Secretion in Pancreatic α-Cells. Int J Mol Sci 2022; 23:4003. [PMID: 35409362 PMCID: PMC8999522 DOI: 10.3390/ijms23074003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 03/28/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.
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Affiliation(s)
- Norikiyo Honzawa
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan; (N.H.); (K.U.); (R.N.)
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Kei Fujimoto
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University Daisan Hospital, 4-11-1, Izumihoncho, Komae-shi, Tokyo 201-8601, Japan
| | - Masaki Kobayashi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Daisuke Kohno
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Osamu Kikuchi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Hiromi Yokota-Hashimoto
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Eri Wada
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Yuichi Ikeuchi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Yoko Tabei
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Gerald W. Dorn
- Center for Pharmacogenomics, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Kazunori Utsunomiya
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan; (N.H.); (K.U.); (R.N.)
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan; (N.H.); (K.U.); (R.N.)
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
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28
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Mima A. Mitochondria-targeted drugs for diabetic kidney disease. Heliyon 2022; 8:e08878. [PMID: 35265754 PMCID: PMC8899696 DOI: 10.1016/j.heliyon.2022.e08878] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/17/2022] [Accepted: 01/30/2022] [Indexed: 12/15/2022] Open
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Mima A. Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages. Eur J Pharmacol 2021; 912:174583. [PMID: 34678238 DOI: 10.1016/j.ejphar.2021.174583] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/17/2022]
Abstract
Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
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30
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El-Kady MM, Naggar RA, Guimei M, Talaat IM, Shaker OG, Saber-Ayad M. Early Renoprotective Effect of Ruxolitinib in a Rat Model of Diabetic Nephropathy. Pharmaceuticals (Basel) 2021; 14:608. [PMID: 34202668 PMCID: PMC8308627 DOI: 10.3390/ph14070608] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 06/23/2021] [Indexed: 01/12/2023] Open
Abstract
Diabetic kidney disease (DKD) is still one of the unresolved major complications of diabetes mellitus, which leads ultimately to end-stage renal disease in both type 1 and type 2 diabetes patients. Available drugs that suppress the renin-angiotensin system have partially minimized the disease impact. Yet, there is an unmet need for new therapeutic interventions to protect the kidneys of diabetic patients. In DN, glomerular sclerosis and tubulointerstitial fibrosis are mediated through several pathways, of which JAK/STAT is a key one. The current study explored the potential renoprotective effect of the JAK1/JAK2 inhibitor ruxolitinib (at doses of 0.44, 2.2, and 4.4 mg·kg-1) compared to that of enalapril at a dose of 10 mg·kg-1, in a rat model of streptozotocin-induced diabetes mellitus over 8 weeks. The effect of ruxolitinib was assessed by determining urinary albumin/creatinine ratio, serum level of cystatin, and levels of TGF-β1, NF-κB, and TNF-α in renal tissue homogenates by biochemical assays, the glomerular sclerosis and tubulointerstitial fibrosis scores by histological analysis, and fibronectin, TGF-β1, and Vimentin levels by immunohistochemical staining with the respective antibodies. Our results revealed a significant early favorable effect of a two-week ruxolitinib treatment on the renal function, supported by a decline in the proinflammatory biomarkers of DKD. This pre-clinical study suggests that the renoprotective effect of ruxolitinib in the long term should be investigated in animals, as this drug may prove to be a potential option for the treatment of diabetic kidney disease.
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Affiliation(s)
- Mohamed M. El-Kady
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo 11559, Egypt;
| | - Reham A. Naggar
- Department of Pharmacology, Faculty of Pharmacy, Misr University for Science and Technology, Giza 12411, Egypt;
| | - Maha Guimei
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt; (M.G.); (I.M.T.)
| | - Iman M. Talaat
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt; (M.G.); (I.M.T.)
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Olfat G. Shaker
- Department of Biochemistry and Molecular Biology, Faculty of Medicine Cairo University, Cairo 11559, Egypt
| | - Maha Saber-Ayad
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
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31
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Imeri F, Stepanovska Tanturovska B, Schwalm S, Saha S, Zeng-Brouwers J, Pavenstädt H, Pfeilschifter J, Schaefer L, Huwiler A. Loss of sphingosine kinase 2 enhances Wilm's tumor suppressor gene 1 and nephrin expression in podocytes and protects from streptozotocin-induced podocytopathy and albuminuria in mice. Matrix Biol 2021; 98:32-48. [PMID: 34015468 DOI: 10.1016/j.matbio.2021.05.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 05/10/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022]
Abstract
The sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that is now appreciated as key regulatory factor for various cellular functions in the kidney, including matrix remodeling. It is generated by two sphingosine kinases (Sphk), Sphk1 and Sphk2, which are ubiquitously expressed, but have distinct enzymatic activities and subcellular localizations. In this study, we have investigated the role of Sphk2 in podocyte function and its contribution to diabetic nephropathy. We show that streptozotocin (STZ)-induced nephropathy and albuminuria in mice is prevented by genetic depletion of Sphk2. This protection correlated with an increased protein expression of the transcription factor Wilm's tumor suppressor gene 1 (WT1) and its target gene nephrin, and a reduced macrophage infiltration in immunohistochemical renal sections of STZ-treated Sphk2-/- mice compared to STZ-treated wildtype mice. To investigate changes on the cellular level, we used an immortalized human podocyte cell line and generated a stable knockdown of Sphk2 (Sphk2-kd) by a lentiviral transduction method. These Sphk2-kd cells accumulated sphingosine as a consequence of the knockdown, and showed enhanced nephrin and WT1 mRNA and protein expressions similar to the finding in Sphk2 knockout mice. Treatment of wildtype podocytes with the highly selective Sphk2 inhibitor SLM6031434 caused a similar upregulation of nephrin and WT1 expression. Furthermore, exposing cells to the profibrotic mediator transforming growth factor β (TGFβ) resulted on the one side in reduced nephrin and WT1 expression, but on the other side, in upregulation of various profibrotic marker proteins, including connective tissue growth factor (CTGF), fibronectin (FN) and plasminogen activator inhibitor (PAI) 1. All these effects were reverted by Sphk2-kd and SLM6031434. Mechanistically, the protection by Sphk2-kd may depend on accumulated sphingosine and inhibited PKC activity, since treatment of cells with exogenous sphingosine not only reduced the phosphorylation pattern of PKC substrates, but also increased WT1 protein expression. Moreover, the selective stable knockdown of PKCδ increased WT1 expression, suggesting the involvement of this PKC isoenzyme in WT1 regulation. The glucocorticoid dexamethasone, which is a treatment option in many glomerular diseases and is known to mediate a nephroprotection, not only downregulated Sphk2 and enhanced cellular sphingosine, but also enhanced WT1 and nephrin expressions, thus, suggesting that parts of the nephroprotective effect of dexamethasone is mediated by Sphk2 downregulation. Altogether, our data demonstrated that loss of Sphk2 is protective in diabetes-induced podocytopathy and can prevent proteinuria, which is a hallmark of many glomerular diseases. Thus, Sphk2 could serve as a new attractive pharmacological target to treat proteinuric kidney diseases.
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Affiliation(s)
- Faik Imeri
- Institute of Pharmacology, University of Bern, Inselspital, INO-F, Bern CH-3010, Switzerland
| | | | - Stephanie Schwalm
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt am Main D-60590, Germany
| | - Sarbari Saha
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt am Main D-60590, Germany
| | - Jinyang Zeng-Brouwers
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt am Main D-60590, Germany
| | - Herrmann Pavenstädt
- Medizinische Klinik D, University Hospital Münster, Münster D-48149, Germany
| | - Josef Pfeilschifter
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt am Main D-60590, Germany
| | - Liliana Schaefer
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt am Main D-60590, Germany.
| | - Andrea Huwiler
- Institute of Pharmacology, University of Bern, Inselspital, INO-F, Bern CH-3010, Switzerland.
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32
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Croteau L, Mercier C, Fafard-Couture É, Nadeau A, Robillard S, Breton V, Guay A, Lizotte F, Despatis MA, Geraldes P. Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb. Diab Vasc Dis Res 2021; 18:1479164121999033. [PMID: 33722087 PMCID: PMC8481738 DOI: 10.1177/1479164121999033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
AIMS Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling. METHODS Nondiabetic and diabetic mice, with (ec-Prkcd-/-) or without (ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs. RESULTS Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd-/- mice. VEGF signaling pathway was restored in diabetic ec-Prkcd-/- mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity. CONCLUSIONS Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.
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Affiliation(s)
- Laura Croteau
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Clément Mercier
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Étienne Fafard-Couture
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Alexandre Nadeau
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Stéphanie Robillard
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Valérie Breton
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Andréanne Guay
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Farah Lizotte
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Marc-Antoine Despatis
- Department of Surgery of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | - Pedro Geraldes
- Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
- Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Sherbrooke, QC, Canada
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Shye M, Hanna RM, Patel SS, Tram-Tran N, Hou J, Mccannel C, Khalid M, Hanna M, Abdelnour L, Kurtz I. Worsening proteinuria and renal function after intravitreal vascular endothelial growth factor blockade for diabetic proliferative retinopathy. Clin Kidney J 2020; 13:969-980. [PMID: 33391740 PMCID: PMC7769550 DOI: 10.1093/ckj/sfaa049] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
Systemic vascular endothelial growth factor (VEGF) inhibitions can induce worsening hypertension, proteinuria and glomerular diseases of various types. These agents can also be used to treat ophthalmic diseases like proliferative diabetic retinopathy, diabetic macular edema, central retinal vein occlusion and age-related macular degeneration. Recently, pharmacokinetic studies confirmed that these agents are absorbed at levels that result in biologically significant suppression of intravascular VEGF levels. There have now been 23 other cases published that describe renal sequela of intravitreal VEGF blockade, and they unsurprisingly mirror known systemic toxicities of VEGF inhibitors. We present three cases where stable levels of proteinuria and chronic kidney disease worsened after initiation of these agents. Two of our three patients were biopsied. The first patient's biopsy showed diabetic nephropathy and focal and segmental glomerulosclerosis (FSGS) with collapsing features and acute interstitial nephritis (AIN). The second patient's biopsy showed AIN in a background of diabetic glomerulosclerosis. This is the second patient seen by our group, whose biopsy revealed segmental glomerulosclerosis with collapsing features in the setting of intravitreal VEGF blockade. Though FSGS with collapsing features and AIN are not the typical lesions seen with systemic VEGF blockade, they have been reported as rare case reports previously. In addition to reviewing known elements of intravitreal VEGF toxicity, the cases presented encompass renal pathology data supporting that intravitreal VEGF blockade can result in deleterious systemic and renal pathological disorders.
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Affiliation(s)
- Michael Shye
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Ramy M Hanna
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Medicine, Division of Nephrology, UCI School of Medicine, Irvine, CA, USA
| | - Sapna S Patel
- Department of Medicine, Division of Nephrology, Long Beach Memorial Medical Center, Long Beach, CA, USA
| | - Ngoc Tram-Tran
- Department of Medicine, Division of Nephrology, Long Beach Memorial Medical Center, Long Beach, CA, USA
| | - Jean Hou
- Department of Pathology, Division of Renal Pathology, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Collin Mccannel
- Department of Ophthalmology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Maham Khalid
- Department of Medicine, Division of Nephrology, UCI School of Medicine, Irvine, CA, USA
| | - Mina Hanna
- School of Medicine, University of Queensland-Ochsner Clinical School, Ochsner Health System, New Orleans, LA, USA
| | - Lama Abdelnour
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Ira Kurtz
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
- Brain Research Center, Los Angeles, CA, USA
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Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy. Int J Mol Sci 2020; 21:ijms21113798. [PMID: 32471207 PMCID: PMC7312633 DOI: 10.3390/ijms21113798] [Citation(s) in RCA: 189] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/20/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury.
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Mima A, Yasuzawa T, Nakamura T, Ueshima S. Linagliptin affects IRS1/Akt signaling and prevents high glucose-induced apoptosis in podocytes. Sci Rep 2020; 10:5775. [PMID: 32238837 PMCID: PMC7113296 DOI: 10.1038/s41598-020-62579-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/16/2020] [Indexed: 11/25/2022] Open
Abstract
Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. High-glucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Osaka Medical College, Osaka, Japan.
| | - Toshinori Yasuzawa
- Department of Health and Nutrition, Faculty of Health Science, Kio University, Nara, Japan.,Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University, Nara, Japan
| | - Tomomi Nakamura
- Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University, Nara, Japan
| | - Shigeru Ueshima
- Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University, Nara, Japan.,Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University, Nara, Japan.,Antiaging Center, Kindai University, Osaka, Japan
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36
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TXNIP deficiency mitigates podocyte apoptosis via restraining the activation of mTOR or p38 MAPK signaling in diabetic nephropathy. Exp Cell Res 2020; 388:111862. [PMID: 31982382 DOI: 10.1016/j.yexcr.2020.111862] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 01/19/2020] [Accepted: 01/22/2020] [Indexed: 12/22/2022]
Abstract
Thioredoxin-interacting protein (TXNIP), is identified as an inhibitor of the thiol oxidoreductase thioredoxin that acts endogenously, and is increased by high glucose (HG). In this study, we investigated the potential function of TXNIP on apoptosis of podocytes and its potential mechanism in vivo and in vitro in diabetic nephropathy (DN). TXNIP silencing attenuated HG-induced apoptosis and obliterated the activation of signaling pathways of mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) in conditionally immortalized mouse podocytes. Furthermore, the Raptor and Rictor shRNAs, mTOR specific inhibitor KU-0063794 and p38 MAPK inhibitor SB203580 were used to assess the role of mTOR or p38 MAPK pathway on podocyte apoptosis induced by HG. The Rictor and Raptor shRNAs and KU-0063794 appeared to reduce HG-induced apoptosis in podocytes. Simultaneously, SB203580 could also restrain HG-induced apoptosis in podocytes. Streptozotocin rendered equivalent diabetes in TXNIP-/- (TKO) and wild-type (WT) control mice. TXNIP deficiency mitigated renal injury in diabetic mice. Additionally, TXNIP deficiency also descended the apoptosis-related protein and Nox4 levels, the mTOR signaling activation and the p38 MAPK phosphorylation in podocytes of diabetic mice. All these data indicate that TXNIP deficiency may mitigate apoptosis of podocytes by inhibiting p38 MAPK or mTOR signaling pathway in DN, underlining TXNIP as a putative target for therapy.
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37
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Denhez B, Rousseau M, Dancosst DA, Lizotte F, Guay A, Auger-Messier M, Côté AM, Geraldes P. Diabetes-Induced DUSP4 Reduction Promotes Podocyte Dysfunction and Progression of Diabetic Nephropathy. Diabetes 2019; 68:1026-1039. [PMID: 30862678 DOI: 10.2337/db18-0837] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 02/25/2019] [Indexed: 11/13/2022]
Abstract
Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease. Hyperglycemia-induced podocyte dysfunction is a major contributor of renal function impairment in DN. Previous studies showed that activation of mitogen-activated protein kinase (MAPK) in diabetes promotes podocyte dysfunction and cell death. Dual specificity phosphatases (DUSPs) are a family of phosphatases mainly responsible for MAPK inhibition. In this study, we demonstrated that diabetes and high glucose exposure decreased DUSP4 expression in cultured podocytes and glomeruli. Diabetes-induced DUSP4 reduction enhanced p38 and c-Jun N-terminal kinase (JNK) activity and podocyte dysfunction. The overexpression of DUSP4 prevented the activation of p38, JNK, caspase 3/7 activity, and NADPH oxidase 4 expression induced by high glucose level exposure. Deletion of DUSP4 exacerbated albuminuria and increased mesangial expansion and glomerular fibrosis in diabetic mice. These morphological changes were associated with profound podocyte foot process effacement, cell death, and sustained p38 and JNK activation. Moreover, inhibition of protein kinase C-δ prevented DUSP4 expression decline and p38/JNK activation in the podocytes and renal cortex of diabetic mice. Analysis of DUSP4 expression in the renal cortex of patients with diabetes revealed that decreased DUSP4 mRNA expression correlated with reduced estimated glomerular filtration rate (<60 mL/min/1.73 m2). Thus, this study demonstrates that preserving DUSP4 expression could protect against podocyte dysfunction and preserve glomerular function in DN.
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Affiliation(s)
- Benoit Denhez
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Marina Rousseau
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | | | - Farah Lizotte
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Andréanne Guay
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Mannix Auger-Messier
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Division of Cardiology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Anne Marie Côté
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Division of Nephrology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Pedro Geraldes
- Research Center of the CHU de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada
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38
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Wang M, Hu J, Yan L, Yang Y, He M, Wu M, Li Q, Gong W, Yang Y, Wang Y, Handy DE, Lu B, Hao C, Wang Q, Li Y, Hu R, Stanton RC, Zhang Z. High glucose-induced ubiquitination of G6PD leads to the injury of podocytes. FASEB J 2019; 33:6296-6310. [PMID: 30785802 DOI: 10.1096/fj.201801921r] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Oxidative stress contributes substantially to podocyte injury, which plays an important role in the development of diabetic kidney disease. The mechanism of hyperglycemia-induced oxidative stress in podocytes is not fully understood. Glucose-6-phosphate dehydrogenase (G6PD) is critical in maintaining NADPH, which is an important cofactor for the antioxidant system. Here, we hypothesized that high glucose induced ubiquitination and degradation of G6PD, which injured podocytes by reactive oxygen species (ROS) accumulation. We found that G6PD protein expression was decreased in kidneys of both diabetic patients and diabetic rodents. G6PD activity was also reduced in diabetic mice. Overexpressing G6PD reversed redox imbalance and podocyte apoptosis induced by high glucose and palmitate. Inhibition of G6PD with small interfering RNA induced podocyte apoptosis. In kidneys of G6PD-deficient mice, podocyte apoptosis was significantly increased. Interestingly, high glucose had no effect on G6PD mRNA expression. Decreased G6PD protein expression was mediated by the ubiquitin proteasome pathway. We found that the von Hippel-Lindau (VHL) protein, an E3 ubiquitin ligase subunit, directly bound to G6PD and degraded G6PD through ubiquitylating G6PD on K366 and K403. In summary, our data suggest that high glucose induces ubiquitination of G6PD by VHL E3 ubiquitin ligase, which leads to ROS accumulation and podocyte injury.-Wang, M., Hu, J., Yan, L., Yang, Y., He, M., Wu, M., Li, Q., Gong, W., Yang, Y., Wang, Y., Handy, D. E., Lu, B., Hao, C., Wang, Q., Li, Y., Hu, R., Stanton, R. C., Zhang, Z. High glucose-induced ubiquitination of G6PD leads to the injury of podocytes.
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Affiliation(s)
- Meng Wang
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Linling Yan
- Department of Endocrinology, The First People's Hospital of Taicang, Suzhou, China
| | - Yeping Yang
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Min He
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Meng Wu
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Qin Li
- Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Wei Gong
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Yang Yang
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Shanghai, China
| | - Yi Wang
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Diane E Handy
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bin Lu
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuanming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qinghua Wang
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.,Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Yiming Li
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
| | - Ronggui Hu
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Shanghai, China
| | - Robert C Stanton
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Zhaoyun Zhang
- Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
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39
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Zeng W, Qi W, Mu J, Wei Y, Yang LL, Zhang Q, Wu Q, Tang JY, Feng B. MG132 protects against renal dysfunction by regulating Akt-mediated inflammation in diabetic nephropathy. Sci Rep 2019; 9:2049. [PMID: 30765727 PMCID: PMC6375942 DOI: 10.1038/s41598-018-38425-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 12/21/2018] [Indexed: 12/25/2022] Open
Abstract
Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD). To date, mounting evidence has shown that inflammation may contribute to the pathogenesis of DN. Recent reports have shown that proteasome inhibitors display cytoprotection by reducing the phosphorylation of Akt, a serine/threonine kinase, plays a critical role in cellular survival and metabolism and can crosstalk with inflammation. Therefore, we hypothesized that MG132, specific proteasome inhibitor, could provide renoprotection by suppressing Akt-mediated inflammation in DN. In vivo, male Sprague-Dawley rats were divided into normal control group (NC), diabetic nephropathy group (DN), DN model plus MG132 treatment group (MG132), and DN model plus deguelin treatment group (Deguelin)(deguelin, a specific inhibitor of Akt). In vitro, a human glomerular mesangial cell lines (HMCs) was exposed to 5.5 mmol/L glucose (CON), 30 mmol/L glucose (HG), 30 mmol/L glucose with 0.5 umol/L MG132 (MG132) and 30 mmol/L glucose with 5 umol/L deguelin (Deguelin). Compared with NC, DN showed a significant increase in the urinary protein excretion rate and inflammatory cytokines, as well as p-Akt. Compared with CON, HMCs co-cultured with HG was notably proliferated, which is in accord with α-smooth muscle actin (α-SMA) expression. These alterations were inhibited by administration of MG132 or deguelin. In conclusion, MG132 significantly inhibits the development of DN by regulating Akt phosphorylation-mediated inflammatory activation.
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Affiliation(s)
- Wei Zeng
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Wei Qi
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Jiao Mu
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Yi Wei
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Li-Ling Yang
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Qian Zhang
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Qiong Wu
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Jian-Ying Tang
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Bing Feng
- Department of Nephrology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
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40
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Hanna RM, Lopez EA, Hasnain H, Selamet U, Wilson J, Youssef PN, Akladeous N, Bunnapradist S, Gorin MB. Three patients with injection of intravitreal vascular endothelial growth factor inhibitors and subsequent exacerbation of chronic proteinuria and hypertension. Clin Kidney J 2018; 12:92-100. [PMID: 30746134 PMCID: PMC6366143 DOI: 10.1093/ckj/sfy060] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 05/28/2018] [Indexed: 12/31/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) receptor inhibition is a commonly used tool to prevent vascular proliferation in tumors and retinal diseases. The antiangiogenic effects of these drugs have made them potent adjunct therapies when given systemically for malignancies. They are also useful tools to ameliorate diminishing eyesight in retinopathy. Hypertension and proteinuria have been observed in systemic VEGF inhibitor therapy, with rarer presentations involving nephrotic-range proteinuria due to glomerulopathies. Pharmacokinetic studies have shown detectable blood levels of anti-VEGF inhibitors up to 30 days postintravitreal injection. Animal studies have also demonstrated binding of VEGF inhibitors in simian glomeruli 1 week after a single intravitreal injection. We report three patients who received intravitreal bevacizumab and/or aflibercept with worsening hypertension, proteinuria and renal injury. Data regarding emerging evidence of VEGF inhibitor nephrotoxicity after intravitreal injections are also presented. The clinical data and the existing literature are reviewed to support the hypothesis that intravitreal anti-VEGF agents may be unrecognized nephrotoxins. These agents are given to vulnerable patients with diabetes, hypertension and preexisting nephropathy and proteinuria. This case series is reported to spur further study of the systemic effects of intravitreal VEGF inhibitors.
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Affiliation(s)
- Ramy M Hanna
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Eduardo A Lopez
- Division of Nephrology, Department of Medicine, Kaiser Permanente Panorama City, Panorama City, CA, USA
| | - Huma Hasnain
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Umut Selamet
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - James Wilson
- Division of Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Peter N Youssef
- Division of Transplant Nephrology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Nermeen Akladeous
- Department of Preventative Medicine, Loma Linda University School of Medicine, Los Angeles, CA, USA
| | - Suphamai Bunnapradist
- Division of Ophthalmology, Department of Surgery, Kaiser Permanente La Palma, La Palma, CA, USA
| | - Michael B Gorin
- Retinal Disorders and Ophthalmic Genetics, Department of Ophthalmology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
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41
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Mima A. Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease. J Diabetes Complications 2018; 32:720-725. [PMID: 29880432 DOI: 10.1016/j.jdiacomp.2018.04.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/23/2018] [Accepted: 04/24/2018] [Indexed: 12/12/2022]
Abstract
AIM Diabetic kidney disease (DKD) is the most frequent cause of mortality and morbidity, leading a global health burden. This review will focus on the potential therapeutic interventions using Sodium-glucose cotransporter-2 (SGLT2) inhibitors that could prevent the development and progression of DKD. RESULTS SGLT2 inhibitors have been widely used as anti-diabetic drugs. Recent clinical studies have demonstrated that these drugs, which improve glycemic control and hypertension and decrease body weight, decrease the risk of renal function impairment and heart failure in patients with type 2 diabetes. With regard to long-term clinical outcomes, the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME), the EMPA-REG Renal OUTCOME, and the CANagliflozin cardioVascular Assessment Study (CANVAS) program which have been integrated from CANVAS and CANVAS-Renal (CANVAS-R) trials reported significant risk reductions in primary combined major adverse cardiovascular events. Furthermore, regarding renal outcomes, the EMPA-REG Renal OUTCOME and CANVAS program clearly showed improvements in renal outcomes, including decreases in albuminuria and progression of nephropathy, doubling of serum creatinine levels, and initiation of renal replacement therapy. CONCLUSIONS Potential mechanisms of SGLT2 inhibitors related to renoprotection can be divided into two categories: hemodynamic actions and metabolic actions.
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Affiliation(s)
- Akira Mima
- Department of Nephrology, Kindai University Faculty of Medicine, Kindai University Nara Hospital, Nara, Japan.
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42
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Preservation of renal function in chronic diabetes by enhancing glomerular glucose metabolism. J Mol Med (Berl) 2018; 96:373-381. [PMID: 29574544 DOI: 10.1007/s00109-018-1630-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/07/2018] [Accepted: 02/12/2018] [Indexed: 12/24/2022]
Abstract
Diabetic nephropathy (DN) affects approximately 30-40% of patients with type 1 (T1DM) and type 2 diabetes (T2DM). It is a major cause of end-stage renal disease (ESRD) for the developed world. Hyperglycemia and genetics are major causal factors for the initiation and progression of DN. Multiple abnormalities in glucose and mitochondrial metabolism induced by diabetes likely contribute to the severity of DN. Recent clinical studies in people with extreme duration of T1DM (> 50 years, Joslin Medalist Study) have supported the importance of endogenous protective factors to neutralize the toxic effects of hyperglycemia on renal and other vascular tissues. Using renal glomeruli from these patients (namely Medalists) with and without DN, we have shown the importance of increased glycolytic flux in decreasing the accumulation of glucose toxic metabolites, improving mitochondrial function, survival of glomerular podocytes, and reducing glomerular pathology. Activation of a key glycolytic enzyme, pyruvate kinase M2 (PKM2), resulted in the normalization of renal hemodynamics and mitochondrial and glomerular dysfunction, leading to the mitigation of glomerular pathologies in several mouse models of DN.
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43
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Mima A, Yasuzawa T, King GL, Ueshima S. Obesity-associated glomerular inflammation increases albuminuria without renal histological changes. FEBS Open Bio 2018; 8:664-670. [PMID: 29632818 PMCID: PMC5881532 DOI: 10.1002/2211-5463.12400] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 01/06/2023] Open
Abstract
Obesity is one of risk factors for chronic kidney disease (CKD), but the precise mechanism involved is unclear. This study characterizes the effect of obesity-induced glomerular inflammation, oxidative stress, and albuminuria in obese rats. Glomerular samples were collected from fatty (ZF) and lean (ZL) Zucker rats. After 2 months of feeding, body weight and albuminuria were significantly increased in ZF rats when compared to ZL rats. Expression of the inflammatory markers TNF-α and CCR2 was significantly increased in the glomeruli of ZF rats. However, expression of IL-6 mRNA was not increased. Analysis of renal pathology showed no glomerular expansion. As inflammatory and oxidative stress markers are associated with NF-κB, we evaluated whether NF-κB activation was increased in the glomeruli of mice on a high-fat diet. Immunohistochemistry showed increased NF-κB activation in the glomeruli when transgenic mice overexpressing an NF-κB-dependent enhanced green fluorescent protein were fed with a high-fat diet. These results suggest that obesity of only 2 months duration can cause albuminuria, due to increased inflammation or oxidative stress, but may not be long enough to develop renal pathological changes.
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Affiliation(s)
- Akira Mima
- Department of Nephrology Kindai University Faculty of Medicine Kindai University Nara Hospital Nara Japan
| | - Toshinori Yasuzawa
- Department of Food Science and Nutrition Faculty of Agriculture Kindai University Nara Japan
| | - George L King
- Research Division Joslin Diabetes Center Harvard Medical School Boston MA USA
| | - Shigeru Ueshima
- Department of Food Science and Nutrition Faculty of Agriculture Kindai University Nara Japan.,Department of Applied Biological Chemistry Graduate School of Agriculture Kindai University Nara Japan.,Antiaging Center Kindai University Osaka Japan
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44
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Sifuentes-Franco S, Padilla-Tejeda DE, Carrillo-Ibarra S, Miranda-Díaz AG. Oxidative Stress, Apoptosis, and Mitochondrial Function in Diabetic Nephropathy. Int J Endocrinol 2018; 2018:1875870. [PMID: 29808088 PMCID: PMC5902001 DOI: 10.1155/2018/1875870] [Citation(s) in RCA: 183] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 02/07/2018] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy (DN) is the second most frequent and prevalent complication of diabetes mellitus (DM). The increase in the production of oxidative stress (OS) is induced by the persistent hyperglycemic state capable of producing oxidative damage to the macromolecules (lipids, carbohydrates, proteins, and nucleic acids). OS favors the production of oxidative damage to the histones of the double-chain DNA and affects expression of the DNA repairer enzyme which leads to cell death from apoptosis. The chronic hyperglycemic state unchains an increase in advanced glycation end-products (AGE) that interact through the cellular receptors to favor activation of the transcription factor NF-κB and the protein kinase C (PKC) system, leading to the appearance of inflammation, growth, and augmentation of synthesis of the extracellular matrix (ECM) in DN. The reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic complications because the production of ROS increases during the persistent hyperglycemia. The primary source of the excessive production of ROS is the mitochondria with the capacity to exceed production of endogenous antioxidants. Due to the fact that the mechanisms involved in the development of DN have not been fully clarified, there are different approaches to specific therapeutic targets or adjuvant management alternatives in the control of glycemia in DN.
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Affiliation(s)
- Sonia Sifuentes-Franco
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, JAL, Mexico
| | - Diego Enrique Padilla-Tejeda
- Programa de Químico Farmacéutico Biotecnologo, Escuela de Ciencias de la Salud, Campus Zapopan, Universidad del Valle de México, Guadalajara, JAL, Mexico
| | - Sandra Carrillo-Ibarra
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, JAL, Mexico
| | - Alejandra Guillermina Miranda-Díaz
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Health Sciences Centre, University of Guadalajara, Guadalajara, JAL, Mexico
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Martin CE, Jones N. Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond. Front Endocrinol (Lausanne) 2018; 9:302. [PMID: 29922234 PMCID: PMC5996060 DOI: 10.3389/fendo.2018.00302] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 05/22/2018] [Indexed: 12/11/2022] Open
Abstract
Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.
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Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BEK, Hughes TM, Craft S, Freedman BI, Bowden DW, Vinik AI, Casellini CM. Diabetic Microvascular Disease: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab 2017; 102:4343-4410. [PMID: 29126250 PMCID: PMC5718697 DOI: 10.1210/jc.2017-01922] [Citation(s) in RCA: 310] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 08/29/2017] [Indexed: 01/18/2023]
Abstract
Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.
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Affiliation(s)
- Eugene J. Barrett
- Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908
| | - Zhenqi Liu
- Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908
| | - Mogher Khamaisi
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
| | - George L. King
- Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
| | - Ronald Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705
| | - Barbara E. K. Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705
| | - Timothy M. Hughes
- Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Suzanne Craft
- Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Barry I. Freedman
- Divisions of Nephrology and Endocrinology, Department of Internal Medicine, Centers for Diabetes Research, and Center for Human Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Donald W. Bowden
- Divisions of Nephrology and Endocrinology, Department of Internal Medicine, Centers for Diabetes Research, and Center for Human Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157
| | - Aaron I. Vinik
- EVMS Strelitz Diabetes Center, Eastern Virginia Medical Center, Norfolk, Virginia 23510
| | - Carolina M. Casellini
- EVMS Strelitz Diabetes Center, Eastern Virginia Medical Center, Norfolk, Virginia 23510
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Qi W, Keenan HA, Li Q, Ishikado A, Kannt A, Sadowski T, Yorek MA, Wu IH, Lockhart S, Coppey LJ, Pfenninger A, Liew CW, Qiang G, Burkart AM, Hastings S, Pober D, Cahill C, Niewczas MA, Israelsen WJ, Tinsley L, Stillman IE, Amenta PS, Feener EP, Vander Heiden MG, Stanton RC, King GL. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med 2017; 23:753-762. [PMID: 28436957 DOI: 10.1038/nm.4328] [Citation(s) in RCA: 353] [Impact Index Per Article: 44.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 03/23/2017] [Indexed: 12/12/2022]
Abstract
Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function.
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Affiliation(s)
- Weier Qi
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Hillary A Keenan
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Qian Li
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Atsushi Ishikado
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Aimo Kannt
- Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
| | | | - Mark A Yorek
- Veterans Affairs Medical Center, Iowa City, Iowa, USA
| | - I-Hsien Wu
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | | - Chong Wee Liew
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Guifen Qiang
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA.,State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, China
| | - Alison M Burkart
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Stephanie Hastings
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - David Pober
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher Cahill
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Monika A Niewczas
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - William J Israelsen
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Liane Tinsley
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Isaac E Stillman
- Beth Israel Deaconess Medical Center, Division of Anatomic Pathology, Boston, Massachusetts, USA
| | - Peter S Amenta
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Edward P Feener
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Robert C Stanton
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - George L King
- Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
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Qi W, Li Q, Liew CW, Rask-Madsen C, Lockhart SM, Rasmussen LM, Xia Y, Wang X, Khamaisi M, Croce K, King GL. SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes. Diabetologia 2017; 60:585-596. [PMID: 27933336 PMCID: PMC5672905 DOI: 10.1007/s00125-016-4159-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 10/28/2016] [Indexed: 01/12/2023]
Abstract
AIMS/HYPOTHESIS Accelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance and diabetes. Elevation of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis in the microvasculature. However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes. METHODS We used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1 expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids. RESULTS Mice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known as Map2k1) and increased DNA methylation of the Shp-1 promoter. VSMCs from Shp-1-Tg mice exhibited impaired platelet-derived growth factor (PDGF)-stimulated tyrosine phosphorylation with a concomitant decrease in PDGF-stimulated VSMC proliferation and migration. Similarly, HFD-fed Shp-1-Tg mice and mice treated with the SHP-1 inducer, Icariside II, were protected from the development of intimal hyperplasia following wire injury. CONCLUSIONS/INTERPRETATION Suppression of SHP-1 by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance. Augmenting SHP-1 levels is a potential therapeutic strategy to maintain stent patency in patients with insulin resistance and diabetes.
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MESH Headings
- Animals
- Blotting, Western
- Cell Cycle/genetics
- Cell Cycle/physiology
- Cell Movement/genetics
- Cell Movement/physiology
- Cell Proliferation/genetics
- Cell Proliferation/physiology
- Humans
- Hyperplasia/metabolism
- Insulin Resistance/genetics
- Insulin Resistance/physiology
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism
- Rats
- Rats, Zucker
- Real-Time Polymerase Chain Reaction
- Tunica Intima/metabolism
- Tunica Intima/pathology
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Affiliation(s)
- Weier Qi
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Qian Li
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Chong Wee Liew
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Christian Rask-Madsen
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Samuel M Lockhart
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Lars Melholt Rasmussen
- Department of Clinical Biochemistry and Pharmacology, Center for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark
| | - Yu Xia
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Xuanchun Wang
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Mogher Khamaisi
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA
| | - Kevin Croce
- Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - George L King
- Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.
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Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017. [PMID: 28639250 DOI: 10.1007/5584_2017_62] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Diabetes is the leading cause of microalbuminuria and end-stage renal failure in industrial countries. Disruption of the filtration barrier, seen in almost all nephrotic diseases and diabetes, is the result of the loss or effacement of the podocyte foot process, notably damage of proteins within the slit diaphragm such as nephrin. For many years, nephrin has been viewed as a structural component of the slit diaphragm. It is now well recognized that nephrin contains several tyrosine residues in its cytoplasmic domain, which influences the development of glomerular injury. In this review, we propose an overview of nephrin signaling pathways in kidney injury.
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