Tubular Mas receptor mediates lipid-induced kidney injury

Yonglun Kong,Weidong Wang,Pinning Feng,Miaojuan Qiu,Suchun Li,Yu Lin,Chunling Li,Hui Huang,Baien Liang,Xiaoduo Zhao,Qing Zhu

doi:10.1038/s41419-020-03375-z

Abstract

Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. The purpose of current study was to investigate the role of Mas receptor in lipid-induced kidney injury. In mice fed with high-fat diet (HFD), the protein abundance of markers of autophagy, endoplasmic reticulum stress (ER stress) and apoptosis was dramatically increased in the kidney cortex, which was markedly prevented by Mas deletion (Mas−/−) or Mas receptor antagonist A779. Palmitic acid (PA) induced persistently increased autophagy, ER stress, and apoptosis as well as mitochondrial injuries in primary cultured proximal tubular cells from wild type, but not from Mas−/− mice. In human proximal tubular HK2 cells, PA-induced autophagy and ER stress was aggravated by Mas agonists Ang (1–7) or AVE0991, but attenuated by A779 or Mas knockdown. Stimulation of Mas resulted in elevated intracellular calcium levels [Ca2+]i in HK2 cells treated with PA, whereas inhibition or knockdown of Mas decreased [Ca2+]i. Mitochondrial outer membrane located voltage-dependent anion channel (VDAC1) was markedly upregulated in HK2 cells treated with PA, which was associated with impaired mitochondrial morphology and depolarization. These were enhanced by AVE0991 and suppressed by A779 or Mas knockdown. Mas knockdown in HK2 cells prevented impaired interactions among VDAC1, autophagy adaptor P62, and ubiquitin, induced by PA, leading to a potential ubiquitination of VDAC1. In conclusion, Mas receptor-mediated lipid-induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries in obesity-related kidney diseases.

Highlights

Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood
These findings strongly suggest that impaired autophagy and accumulation of autophagic bodies induced by palmitic acid (PA) may be the cause of ER stress and later cell death in HK2 cells
Mas knockdown suppressed PA-induced upregulation of ubiquitin, VDAC1 and P62 protein (Fig. 7E), but promoted the interaction between P62 and VDAC1 (Fig. 7F), and the interaction between VDAC1 and ubiquitin (Fig. 7G), respectively. These results suggested that Mas signaling probably mediates an incomplete ubiquitination of VDAC1-P62 complex in HK2 cells treated with PA

Summary

Introduction

Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. Accumulation of saturated free fatty acid and their metabolites within renal epithelial cells produces lipotoxicity, resulting in significant cellular dysfunction and injuries. It is well known that renin-angiotensin system (RAS) plays a crucial role in obesity-related kidney diseases. Each RAS component has been identified in the kidney, suggesting the role of the local/tissue and intracellular RAS in the development and progression of renal diseases. We have recently demonstrated that blockade of RAS with direct renin inhibitor aliskiren, angiotensin-II type 1 receptor blocker valsartan, or chymase inhibitor chymostatin effectively attenuated tubular epithelial cell. Kong et al Cell Death and Disease (2021)12:110 injuries induced by saturated fatty acid palmitic acid (PA) or high-fat diet (HFD) in mice. As an alternative pathway of the RAS, angiotensin 1–7 (Ang [1,2,3,4,5,6,7]) and its G-protein coupled receptor Mas (encoded by Mas gene, named as Mrgprs, the term “Mas” was used in the present article) has been extensively examined

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