Mitochondrial dysfunction mediates aldosterone-induced podocyte damage: a therapeutic target of PPARγ.

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-γ (PPARγ) coactivator-1α and mt transcription factor A. Both the PPARγ agonist rosiglitazone and PPARγ 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 PPARγ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPARγ agonist rosiglitazone may protect podocytes from this injury by improving mitochondrial function.

Zhu C ，Huang S ，Yuan Y ，Ding G ，Chen R ，Liu B ，Yang T ，Zhang A ... -  《-》

Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury.

Su M ，Dhoopun AR ，Yuan Y ，Huang S ，Zhu C ，Ding G ，Liu B ，Yang T ，Zhang A ... -  《-》

PGC-1α overexpression protects against aldosterone-induced podocyte depletion: role of mitochondria.

Zhao M ，Yuan Y ，Bai M ，Ding G ，Jia Z ，Huang S ，Zhang A ... -  《Oncotarget》

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

Yuan Y ，Huang S ，Wang W ，Wang Y ，Zhang P ，Zhu C ，Ding G ，Liu B ，Yang T ，Zhang A ... -  《-》

MicroRNA-30e targets BNIP3L to protect against aldosterone-induced podocyte apoptosis and mitochondrial dysfunction.

MicroRNAs are essential for the maintenance of podocyte homeostasis. Emerging evidence has demonstrated a protective role of microRNA-30a (miR-30a), a member of the miR-30 family, in podocyte injury. However, the roles of other miR-30 family members in podocyte injury are unclear. The present study was undertaken to investigate the contribution of miR-30e to the pathogenesis of podocyte injury induced by aldosterone (Aldo), as well as the underlying mechanism. After Aldo treatment, miR-30e was reduced in a dose-and time-dependent manner. Notably, overexpression of miR-30e markedly attenuated Aldo-induced apoptosis in podocytes. In agreement with this finding, miR-30e silencing led to significant podocyte apoptosis. Mitochondrial dysfunction (MtD) has been shown to be an early event in Aldo-induced podocyte injury. Here we found that overexpression of miR-30e improved Aldo-induced MtD while miR-30e silencing resulted in MtD. Next, we found that miR-30e could directly target the BCL2/adenovirus E1B-interacting protein 3-like (BNIP3L) gene. Aldo markedly enhanced BNIP3L expression in podocytes, and silencing of BNIP3L largely abolished Aldo-induced MtD and cell apoptosis. On the contrary, overexpression of BNIP3L induced MtD and apoptosis in podocytes. Together, these findings demonstrate that miR-30e protects mitochondria and podocytes from Aldo challenge by targeting BNIP3L.

Guo Y ，Deng X ，Chen S ，Yang L ，Ni J ，Wang R ，Lin J ，Bai M ，Jia Z ，Huang S ，Zhang A ... -  《-》