Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury

Abstract

Glomerular podocytes are highly specialized epithelial cells whose injury in glomerular diseases causes proteinuria. Since mitochondrial dysfunction is an early event in podocyte injury, we tested whether a major regulator of oxidative metabolism and mitochondrial function, the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), affects podocyte damage. Aldosterone-induced injury decreased PGC-1α expression, and induced mitochondrial and podocyte damage in dose- and time-dependent manners. The suppression of endogenous PGC-1α by RNAi caused podocyte mitochondrial damage and apoptosis while its increase by infection with an adenoviral vector prevented aldosterone-induced mitochondrial malfunction and inhibited injury. Overexpression of the silent mating type information regulation 2 homolog 1, a gene upstream of PGC-1α, prevented aldosterone-induced mitochondrial damage and podocyte injury by upregulating PGC-1α at both the transcriptional and post-translational levels. Resveratrol, a SIRT1 activator, attenuated aldosterone-induced mitochondrial malfunction and podocyte injury in vitro and in aldosterone-infused mice in vivo. Hence, endogenous PGC-1α may be important for maintenance of mitochondrial function in podocytes under normal conditions. Activators of SIRT1, such as resveratol, may be therapeutically useful in glomerular diseases to promote and maintain PGC-1α expression and, consequently, podocyte integrity.

Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy

“…Our results reinforce the importance of mitochondria as one of the key components of this complex and a major part of the multifactorial complications of diabetes (9,10,38,39). This study underscores previous observations by our group and others that improving mitochondrial function, by targeting mitochondrial dynamics, activity, or numbers, is renoprotective in different models of kidney injury, including DN (12,(40)(41)(42)(43)(44)(45)(46)(47)(48). We provide evidence that PGC-1α is a mechanistic target of Tug1 in podocytes in the kidney, through which Tug1 regulates mitochondrial bioenergetics.…”

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…Similar, rosiglitazone was observed to attenuate the development of proteinuria and glomerulosclerosis in doxorubicin-induced FSGS in rats [72]. Rosiglitazone is able to protect podocytes against damage caused by mitochondrial dysfunction [73]. Moreover, TZDs can prevent actin filament redistribution induced by PAN [74] and directly influence expression of small ubiquitin-like modifiers (SUMOs) [75], which we recently demonstrated are essential for the cellular surface expression of nephrin in podocytes (Fig.…”

“…Positive (diabetes) [55]/ negative (other glomerular disease) [56,57] Actin cytoskeleton, VEGF [53,61], synaptopodin, podocin, nephrin, apoptosis [60] Glitazones (PPARγ agonists) Positive SUMOs [75], mitochondrial function [73] Glucocorticoids Positive Glucocorticoid receptor, gene expression, actin rearrangement [34][35][36] RAAS blockade (ACE inhibitor, AT1-R blocker) Positive AT1-R, actin cytoskeleton [23,24], ZO-1 [28] Rituximab (CD20 antibody)…”

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

“…21 We then examined the effects of ER stress on aldosterone induced podocyte injury. Histopathologically, treatment of PBA inhibited the glomerular mesangial cell proliferation by aldosterone (Figure 1c and d).…”