Tubular Mas receptor mediates lipid-induced kidney injury

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.

A multi‐omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells

“…To investigate whether this could be occurring in our cEV treated normal cells, we treated HPDE-H6c7 ERSE luciferase reporter cells with various concentrations of palmitic acid. We found that ER stress was induced at 75 μM (Figure 7c), well below commonly reported doses of 250-500 μM and higher in other cell types (Ben-Dror & Birk, 2019; Kong et al, 2021). We confirmed upregulation of DDIT3 protein 24 h after treatment with 75 μM of palmitic acid (Figure 7d).…”

A multi-omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells

“…We found that ER stress was induced at 75 µM (Fig. 6c), well below commonly reported doses of 250 µM -500 µM and higher in other cell types 44,45 . This suggests that enrichment of palmitic acid in cEVs may induce ER stress in part, leading to activation of the UPR in treated normal cells.…”

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

“…In contrast to the studies that suggest a protective role for the ACE2/Ang-(1-7)/Mas receptor axis, accumulating evidence suggests that downregulation of this pathway may be beneficial in disease settings. For example, genetic and pharmacological Mas receptor deficiency has been reported to prevent high-fat diet–induced kidney injury ( Kong et al, 2021 ), abolish salt-sensitive hypertension ( Heringer-Walther et al, 2012 ), reduce kidney damage in models of kidney injury (e.g., unilateral ureteral obstruction and ischemia/reperfusion injury) ( Esteban et al, 2009 ), and inhibit NF- κ B activation and thus the upregulation of proinflammatory cytokines ( Esteban et al, 2009 ). Clearly, more studies are needed to establish the contribution of the ACE2/Ang-(1-7)/Mas receptor axis in kidney health and disease, also in view of the fact that recent studies do not support that Ang-(1-7) is the endogenous agonist of the Mas receptor ( Gaidarov et al, 2018 ).…”