Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney

Carmen De Miguel,David M Pollock,Janet L Hobbs,William C Hamrick,Pamela K Carmines,Jennifer S Pollock

doi:10.1038/srep43152

Abstract

Endothelin-1 (ET-1) promotes renal damage during cardiovascular disease; yet, the molecular mechanisms involved remain unknown. Endoplasmic reticulum (ER) stress, triggered by unfolded protein accumulation in the ER, contributes to apoptosis and organ injury. These studies aimed to determine whether the ET-1 system promotes renal ER stress development in response to tunicamycin. ETB deficient (ETB def) or transgenic control (TG-con) rats were used in the presence or absence of ETA receptor antagonism. Tunicamycin treatment similarly increased cortical ER stress markers in both rat genotypes; however, only ETB def rats showed a 14–24 fold increase from baseline for medullary GRP78, sXBP-1, and CHOP. Pre-treatment of TG-con rats with the ETA blocker ABT-627 for 1 week prior to tunicamycin injection significantly reduced the ER stress response in cortex and medulla, and also inhibited renal apoptosis. Pre-treatment with ABT-627 failed to decrease renal ER stress and apoptosis in ETB def rats. In conclusion, the ET-1 system is important for the development of tunicamycin-induced renal ER stress and apoptosis. ETA receptor activation induces renal ER stress genes and apoptosis, while functional activation of the ETB receptor has protective effects. These results highlight targeting the ETA receptor as a therapeutic approach against ER stress-induced kidney injury.

Highlights

Upregulation of the endothelin (ET) system has been reported in a wide range of cardiovascular and renal diseases[1,2]; the exact cellular and molecular mechanisms through which endothelin-1 (ET-1) leads to renal injury are not fully discerned
The present study demonstrates that the ETA and ETB receptors play opposite roles in the development of endoplasmic reticulum (ER) stress and apoptosis in the kidney in response to tunicamycin
Activation of the ETA receptor is important for tunicamycin-induced ER stress and apoptosis in the kidney as well as increased albumin excretion, and, on the other hand, activation of the ETB receptor ameliorates and is necessary for the protection against the renal injury by inhibiting ER stress and renal apoptosis

Summary

Introduction

Upregulation of the endothelin (ET) system has been reported in a wide range of cardiovascular and renal diseases[1,2]; the exact cellular and molecular mechanisms through which endothelin-1 (ET-1) leads to renal injury are not fully discerned. Evidence in the literature demonstrates an important role of ER stress in the development of acute kidney injury (AKI) in humans and in animal models of this disease[6,7,8] Both ET-1 and ER stress are upregulated in renal diseases such as contrast-induced acute kidney injury[9,10], ischemia/reperfusion injury[11,12], septic shock-induced acute kidney injury[13,14], and diabetic nephropathy[15,16], suggesting that overactivation of the ET-1 system may lead to induction of the renal ER stress response. There are contradictory reports in the literature regarding the role that ET-1 plays in the development of apoptosis and renal injury, with some reports indicating that ET-1 induces cellular apoptosis[21,22] and others suggesting the opposite[23,24,25]

Methods

Results

Conclusion