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Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F520-31. doi: 10.1152/ajprenal.00570.2012. Epub 2013 Jun 12.

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

Author information

1
Dept. of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing Medical Univ., 72 Guangzhou Road, Nanjing 210029, Jiangsu Province, P. R. of China. zhaihua@njmu.edu.cn.

Abstract

We previously showed that mitochondrial dysfunction (MtD) is involved in an aldosterone (Aldo)-induced podocyte injury. Here, the potential role of MtD in the initiation of podocyte damage was investigated. We detected the dynamic changes of urinary protein, urinary F2-isoprostane and renal malondialdehyde levels, kidney ultrastructure morphology, mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (ΔΨm), and nephrin and podocin expressions in Aldo-infused mice. Aldo infusion first induced renal oxidative stress, as evidenced by increased levels of urinary F2-isoprostane and renal malondialdehyde, and MtD, as demonstrated by reduced mtDNA, ΔΨm, and ATP production. Later, at 5 days after Aldo infusion, proteinuria and podocyte injury began to appear. In cultured podocytes, Aldo or hydrogen peroxide (H2O2) induced MtD after 2-8 h of treatment, whereas the podocyte damage, as shown by decreased nephrin and podocin expressions, occurred later after 12 h of treatment. Thus Aldo treatment both in vitro and in vivo indicated that MtD occurred before podocyte damage. Additionally, MtDNA depletion by ethidium bromide or mitochondrial transcription factor A (TFAM) RNAi induced MtD, further promoting podocyte damage. TFAM expression was found to be reduced in Aldo-infused mice and Aldo-treated podocytes. Adenoviral vector-mediated overexpression of TFAM prevented Aldo-induced MtD and protected against podocyte injury. Together, these findings support MtD as an early event in podocyte injury, and manipulation of TFAM may be a novel strategy for treatment of glomerular diseases such as podocytopathy.

KEYWORDS:

aldosterone; mitochondria; mitochondrial transcription factor A; podocytes

PMID:
23761667
DOI:
10.1152/ajprenal.00570.2012
[Indexed for MEDLINE]
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