Mild electrical stimulation with heat shock attenuates renal pathology in adriamycin-induced nephrotic syndrome mouse model

Keisuke Teramoto,Mary Ann Suico,Shota Kaseda,Kohei Omachi,Eiichi Araki,Hirofumi Kai,Tsuyoshi Shuto,Yu Tsurekawa,Tsubasa Yokota,Misato Kamura,Tatsuya Kondo,Mariam Piruzyan

doi:10.1038/s41598-020-75761-8

Abstract

Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. One of the main causes of NS is focal segmental glomerulosclerosis (FSGS), which has extremely poor prognosis. Although steroids and immunosuppressants are the first line of treatment, some FSGS cases are refractory, prompting the need to find new therapeutic strategies. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. Here, we investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS suppressed proteinuria and glomerulosclerosis induced by ADR. The expressions of pro-inflammatory cytokines and pro-fibrotic genes were also significantly downregulated by MES + HS. MES + HS decreased the expression level of cleaved caspase-3 and the number of TUNEL-positive cells, indicating that MES + HS exerted anti-apoptotic effect. Moreover, MES + HS activated the Akt signaling and induced the phosphorylation and inhibition of the apoptotic molecule BAD. In in vitro experiment, the Akt inhibitor abolished the MES + HS-induced Akt-BAD signaling and anti-apoptotic effect in ADR-treated cells. Collectively, our study suggested that MES + HS modulates ADR-induced pathologies and has renoprotective effect against ADR-induced NS via regulation of Akt-BAD axis.

Highlights

Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema
focal segmental glomerulosclerosis (FSGS) is caused by loss of podocytes due to cell damage or a poptosis[33,34] and is sometimes found in chronic kidney disease (CKD)
We revealed that mild electrical stimulation (MES) + heat shock (HS) ably suppressed proteinuria and glomerulosclerosis in ADR-induced FSGS mouse model

Summary

Introduction

Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. We investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS attenuates these disease conditions mostly by modulating injury, fibrosis and the immune response through suppression of cytokines and fibrotic factors via multiple signaling pathways such as the PI3K-Akt, mitogen-activated protein kinases (MAPKs) and transforming growth factor (TGF)-β, among others. We investigated the effects of MES + HS on NS using adriamycin (ADR; called doxorubicin)-induced NS mouse m odel[24] This model is known to be accompanied by FSGS. MES + HS suppressed the NS-induced apoptosis via regulating Akt-BAD axis, indicating the potential of MES + HS as a novel therapeutic modality for NS

Methods

Results

Conclusion