RTN1 mediates progression of kidney disease by inducing ER stress.

Ying Fan,Peter Y Chuang,Belinda Jim,Wenzhen Xiao,Kyung Lee,Huabao Xiong,Weijia Zhang,Chengguo Wei,Niansong Wang,Weiping Jia,Zhengzhe Li,Xuezhu Li,John C He

doi:10.1038/ncomms8841

Abstract

Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Here we report an association between expression of reticulon 1 (RTN1) and severity of CKD. An isoform-specific increase in the expression of RTN1A is detected in the diseased kidneys from mice and humans, and correlates inversely with renal function in patients with diabetic nephropathy. RTN1 overexpression in renal cells induces ER stress and apoptosis, whereas RTN1 knockdown attenuates tunicamycin-induced and hyperglycaemia-induced ER stress and apoptosis. RTN1A interacts with PERK through its N-terminal and C-terminal domains, and mutation of these domains prevents this effect on ER stress. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and also attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress.

Highlights

Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy
Previous studies in the neurons suggested that reticulon 1 (RTN1) might be involved in endoplasmic reticulum (ER) stress and apoptosis, which are key pathologic processes leading to the progression of CKD11,12
Since Tg26 mice exhibit variable severity of renal phenotypes ranging from rapid progression to renal failure to mild disease with stable renal function for 46 months, it is an ideal system for studying factors that dictate kidney disease progression[13]

Summary

Introduction

Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress. We report that the expression of RTN1, RTN1A isoform, is highly upregulated in both human and mouse models with kidney disease, and that its increased expression induces ER stress response and apoptosis in renal cells. Reduction of RTN1A expression in vivo results in attenuation of renal fibrosis and diabetic kidney injury, which is associated with decreased ER stress markers, indicating that RTN1A is a novel mediator of CKD progression that promotes renal injury through ER stress

Methods

Results

Conclusion