Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Abstract

Aldosterone (Aldo) causes podocyte damage by an unknown mechanism. We examined the role of mitochondrial dysfunction (MtD) in Aldo-treated podocytes in vitro and in vivo. Exposure of podocytes to Aldo reduced nephrin expression dose dependently, accompanied by increased production of reactive oxygen species (ROS). The ROS generation and podocyte damage were abolished by the mitochondrial (mt) respiratory chain complex I inhibitor rotenone. Pronounced MtD, including reduced mt membrane potential, ATP levels, and mtDNA copy number were seen in Aldo-treated podocytes and in the glomeruli of Aldo-infused mice. The mineralocorticoid receptor antagonist eplerenone significantly inhibited Aldo-induced MtD. The MtD was associated with higher levels of ROS, reduction in the activity of complexes I, III, and IV, and expression of the peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator-1␣ and mt transcription factor A. Both the PPAR␥ agonist rosiglitazone and PPAR␥ overexpression protected against podocyte injury by preventing MtD and oxidative stress, as evidenced by reduced ROS production, by maintenance of mt morphology, by restoration of mtDNA copy number, by decrease in mt membrane potential loss, and by recovery of mt electron transport function. The protective effect of rosiglitazone was abrogated by the specific PPAR␥ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPAR␥ agonist rosiglitazone may protect podocytes from this injury by The mineralocorticoid aldosterone (Aldo) is a key component of the renin-angiotensin-aldosterone system and is increasingly recognized as an important player in the development and progression of kidney disease. Patients with chronic kidney disease have markedly elevated plasma Aldo concentrations. Animal studies suggest that Aldo is a pathogenic factor in renal injury in the remnant kidney of hypertensive rats, 1 and in renal fibrosis. Moreover, exogenous infusion of Aldo reverses the renoprotective effects of angiotensin-converting enzyme inhibitors in hypertensive remnant kidney rats, and in stroke-prone, spontaneously hypertensive rats. 2 In vitro studies show that Aldo exerts a direct deleterious influence on kidney cells, including podocytes, 3-5 mesangial cells, proximal tubular epithelial cells, 6 and fibroblasts. In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury. 5,[7][8][9] However, the underlying mechanism for Aldoinduced injury in the kidney (in general) and in the podocytes (in particular) is not well understood.Podocytes are terminally differentiated, high-energy required cells that have lost mitotic activity, and typically do not proliferate after injury. 10 Mitochondria (mt) dysfunction (MtD) is involved in several diseases and progressive disease processes, including glomerulosclerosis, in which podocyte injury is a crucial event in sclerosis formation. 11,12 We hypothesized that preserving mt func...

Mitochondrial dysfunction in the pathophysiology of renal diseases

“…We described that mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury. In an aldosterone-infused mouse model, before fusion of podocyte processes and proteinuria, the mitochondrial membrane potential, copy number of mtDNA, and ATP production start to decease with the increase in ROS production (130,160). In addition, mitochondrial dynamics and quality control processes are involved in podocyte injury.…”

“…For example, they were able to reduce proteinuria and fibrotic responses and prevent podocyte as well as vascular injury, in both animal and clinical trials (87,121). Rosiglitazone, one of the TZDs, can effectively inhibit podocyte injury and MC proliferation through reduced ROS production and recovery of mitochondrial electron transport function in vivo and in vitro (65,154,160). TZDs also decrease TGF-␤ production in glomeruli, thus attenuating renal interstitial fibrosis (74).…”

Loss of Krüppel-like factor 6 cripples podocyte mitochondrial function

“…Other new therapeutic approaches are also being explored. For example, PPARα protects podocytes from aldosterone-induced mitochondrial dysfunction (32). Glycogen synthetase kinase (GSK) 3β integrates signals that regulate mitochondrial pore transition, and a thiazolidinedione compound that inhibits GSK2β was shown to alleviate doxorubicin-induced podocyte injury in vitro and in vivo (33).…”

Ginsenoside Rg1 protects mouse podocytes from aldosterone-induced injury in vitro

“…Shibata et al [13] observed podocyte injury following increased NADPH oxidase activity in the kidney of aldosterone-infused rats. Another study found that mitochondria dysfunction was associated with higher levels of ROS production and was involved in aldosterone-induced podocyte injury [14,15] . ROS are scavenged by a sophisticated antioxidant defense system that includes enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSHPx).…”