Protective role of Trpc6 knockout in the progression of diabetic kidney disease

Diabetic kidney disease (DKD) is a chronic kidney pathology that leads to end-stage renal disease. Previous studies from our laboratory indicate that there is an association between the development of DKD and the transient receptor potential canonical 6 (TRPC6) channel. Trpc6 expression and activity were increased in the streptozotocin (STZ)-treated Dahl Salt-sensitive (Dahl SS) rat, an established model of type 1 diabetes. Here, using a Trpc6 knockout created on the Dahl SS rat background (SSTrpc6−/−), we test the hypothesis that the absence of Trpc6 will protect podocytes and kidney function during the development of DKD. Four groups of animals (control SSWT, SSTrpc6−/−, STZ-treated SSWT, and STZ-SSTrpc6−/−) were utilized in this study. Diabetes development was monitored for 11 wk after STZ injection with periodic weight, glucose, and urinary output measurements. There was an increase in albuminuria and glomerular injury following STZ treatment, which was not different between Dahl SS and SSTrpc6−/− groups. Western blot analysis revealed elevated levels of nephrin in urine samples of STZ-SSWT rats, which was higher compared with STZ-SSTrpc6−/− rats. Furthermore, pathological increases in basal [Ca2+]i levels and foot process damage of podocytes during the development of DKD was attenuated in the STZ-SSTrpc6−/− compared with STZ-SSWT rats. Overall, our data indicate that TRPC6 channel inhibition may have at least partial renoprotective effects, which could lead to the development of new pharmacological tools to treat or prevent the progression of DKD.

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Role of Transient Receptor Potential Canonical Channel 6 (TRPC6) in Diabetic Kidney Disease by Regulating Podocyte Actin Cytoskeleton Rearrangement

Journal of Diabetes Research ◽

10.1155/2020/6897390 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Qian Wang ◽

Xuefei Tian ◽

Yuyang Wang ◽

Yan Wang ◽

Jialin Li ◽

...

Keyword(s):

Kidney Disease ◽

Actin Cytoskeleton ◽

Diabetic Kidney Disease ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Diabetic Kidney ◽

Transient Receptor Potential Canonical ◽

Transient Receptor ◽

Cytoskeleton Rearrangement

Podocyte injury is an important pathogenesis step causing proteinuric kidney diseases such as diabetic kidney disease (DKD). Actin cytoskeleton rearrangement in podocyte induced by multiple pathogenic factors is believed to be the key process resulting in glomerular injury. Many studies have recently shown that transient receptor potential canonical channel 6 (TRPC6) in podocyte plays a critical role in the development and progression of proteinuric kidney disease by regulating its actin cytoskeleton rearrangement. This review is aimed at summarizing the role of TRPC6 on DKD by regulating the podocyte actin cytoskeleton rearrangement, thereby help further broaden our views and understanding on the mechanism of DKD and provide a theoretic basis for exploring new therapeutic targets for DKD patients.

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Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

Journal of Clinical Medicine ◽

10.3390/jcm10102046 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2046

Author(s):

Goren Saenz-Pipaon ◽

Saioa Echeverria ◽

Josune Orbe ◽

Carmen Roncal

Keyword(s):

Kidney Disease ◽

Extracellular Vesicles ◽

Diabetic Kidney Disease ◽

Current Knowledge ◽

Developed Countries ◽

Disease Diagnosis ◽

Renal Diseases ◽

Diabetic Kidney ◽

Glucose Levels ◽

Stage Renal Disease

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

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Therapeutic Strategies for Diabetic Kidney Disease

Diabetology ◽

10.3390/diabetology2010003 ◽

2021 ◽

Vol 2 (1) ◽

pp. 31-35

Author(s):

Keiichiro Matoba

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Intensive Therapy ◽

Therapeutic Strategies ◽

Therapeutic Interventions ◽

Hemodynamic Changes ◽

Diabetic Kidney ◽

Global Epidemic ◽

Stage Renal Disease ◽

End Stage

Diabetic kidney disease (DKD) is a global epidemic leading to end-stage renal disease (ESRD) and susceptibility to cardiovascular disease, with few therapeutic interventions. A hallmark of DKD is the activation of the renin-angiotensin-aldosterone system and hemodynamic changes in glomerulus. Although intensive therapy with agents that targets those abnormalities lowers the risk of DKD progression, it does not completely abolish the risk of ESRD and cardiovascular events. Recent studies have illustrated the importance of renal inflammation, oxidative stress, and activated Rho-associated protein kinase (ROCK) signaling as essential pathogenesis for the development of DKD. In this commentary, these topics will be discussed.

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Diabetic kidney disease in thedb/dbmouse

AJP Renal Physiology ◽

10.1152/ajprenal.00315.2002 ◽

2003 ◽

Vol 284 (6) ◽

pp. F1138-F1144 ◽

Cited By ~ 267

Author(s):

Kumar Sharma ◽

Peter McCue ◽

Stephen R. Dunn

Keyword(s):

Diabetic Nephropathy ◽

Kidney Disease ◽

Mouse Model ◽

Renal Disease ◽

Mouse Models ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Matrix Expansion ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

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Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats

Physiological Genomics ◽

10.1152/physiolgenomics.00009.2021 ◽

2021 ◽

Author(s):

Denisha R Spires ◽

Oleg Palygin ◽

Vladislav Levchenko ◽

Elena Isaeva ◽

Christine A. Klemens ◽

...

Keyword(s):

Sexual Dimorphism ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

Disease Risk ◽

Plasma Cholesterol ◽

Cardiovascular Disease Risk ◽

Glomerular Injury ◽

Diabetic Kidney ◽

Age Related

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end-stage renal failure and increases cardiovascular disease risk. Hyperglycemia promotes renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity- and age-related risk factors. This study aimed to define sexual dimorphism and renal function in a non-obese type 2 diabetes model with the spontaneous development of advanced diabetic nephropathy (T2DN rats). T2DN rats at 12- and over 48-weeks old were used to define disease progression and kidney injury development. We found impaired glucose tolerance and glomerular hyperfiltration in T2DN rats to compare with non-diabetic Wistar control. The T2DN rat displays a significant sexual dimorphism in insulin resistance, plasma cholesterol, renal and glomerular injury, urinary nephrin shedding, and albumin handling. Our results indicate that both male and female T2DN rats developed non-obese type 2 DKD phenotype, where the females had significant protection from the development of severe forms of DKD. Our findings provide further evidence for the T2DN rat strain's effectiveness for studying the multiple facets of DKD.

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Urinary Markers of Glomerular Injury in Diabetic Nephropathy

International Journal of Nephrology ◽

10.1155/2012/146987 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 32

Author(s):

Abraham Cohen-Bucay ◽

Gautham Viswanathan

Keyword(s):

Renal Failure ◽

Diabetic Nephropathy ◽

Kidney Disease ◽

Current Literature ◽

Cardiovascular Events ◽

Diabetic Kidney Disease ◽

Glomerular Injury ◽

Diabetic Kidney ◽

Urinary Markers

Diabetic nephropathy, the leading cause of renal failure worldwide, affects approximately one-third of all people with diabetes. Microalbuminuria is considered the first sign and the best predictor of progression to renal failure and cardiovascular events. However, albuminuria has several limitations. Therefore, earlier, more sensitive and specific biomarkers with greater predictability are needed. The aim of this paper is to discuss the current literature on biomarkers of glomerular injury that have been implicated in diabetic kidney disease.

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Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz168 ◽

2019 ◽

Cited By ~ 4

Author(s):

Yu Ho Lee ◽

Ki Pyo Kim ◽

Sun-Hwa Park ◽

Dong-Jin Kim ◽

Yang-Gyun Kim ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Interstitial Fibrosis ◽

Renal Outcome ◽

Enzyme Linked Immunosorbent Assay ◽

Glomerular Injury ◽

Tubular Atrophy ◽

Diabetic Kidney ◽

Cytokines And Chemokines ◽

Pathologic Features

Abstract Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P = 0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

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