Abstract

Objective Abnormal signaling pathways play a crucial role in the mechanisms of podocyte injury in diabetic nephropathy. They also affect the recovery of podocytes after islet transplantation (IT). However, the specific signaling abnormalities that affect the therapeutic effect of IT on podocytes remains unclear. The purpose of this study was to assess whether the RhoA/ROCK/NF-κB signaling pathway is related to podocyte restoration after IT. Methods A mouse model of diabetic nephropathy was established in vivo using streptozotocin. The mice were then subsequently reared for 4 weeks after islet transplantation to determine the effect of IT. Islet cells, CCG-1423 (RhoA Inhibitor), and fasudil (ROCK inhibitor) were then cocultured with podocytes in vitro to assess their protective effects on podocyte injury induced by high glucose (HG). Protein expression levels of RhoA, ROCK1, synaptopodin, IL-6, and MCP-1 in kidney tissues were then measured using immunohistochemistry and Western blotting techniques. Results Islet transplantation reduced the expression levels of RhoA/ROCK1 and that of related inflammatory factors such as IL-6 and MCP-1 in the kidney podocytes of diabetic nephropathy. In the same line, islet cells reduced the expression of RhoA, ROCK1, and pp65 in immortalized podocytes under high glucose (35.0 mmol/L glucose) conditions. Conclusions Islet transplantation can reverse podocyte injury in diabetes nephropathy by inhibiting the RhoA/ROCK1 signaling pathway. Islet cells have a strong protective effect on podocytes treated with high glucose (35.0 mmol/L glucose). Discovery of signaling pathways affecting podocyte recovery is helpful for individualized efficacy evaluation and targeted therapy of islet transplantation patients.

Highlights

  • Diabetic nephropathy (DN) is a serious microvascular complication that causes end-stage renal disease [1]

  • The level of urine protein-to-creatinine, urea nitrogen, and blood creatinine decreased significantly in the islet transplantation (IT) group compared to untreated DN mice (Figures 2(c)–2(e))

  • The increased expression of pp65 induced by high glucose (HG) (35.0 mmol/L glucose) was inhibited by fasudil. This indicated that NF-κB expression was mediated by the RhoA/ROCK signaling pathway (Figures 6(f) and 6(g)). These findings demonstrated that islet cells and fasudil reversed the HG (35.0 mmol/L glucose) induced low synaptopodin expression by inhibiting expression of the RhoA/ROCK1/NF-κB pathway

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Summary

Introduction

Diabetic nephropathy (DN) is a serious microvascular complication that causes end-stage renal disease [1]. It is characterized by appearance of progressive proteinuria, glomerular filtration injury, glomerular sclerosis, and glomerular basement membrane (GBM) thickening. Podocytes are essential components of glomerular filtration barrier function. An injury to podocytes results to the development of proteinuria [2]. Podocyte injury is one of the most important mechanisms that lead to DN [3]. Cognizant to this, reversing podocyte injury is a promising therapeutic target for DN patients

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