title: Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury.
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.
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.forename: Asish-Roopchand
authors.initials: AR
authors.lastname: Dhoopun
authors.forename: Yanggang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhu
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.forename: Bicheng
authors.initials: B
authors.lastname: Liu
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D004272:DNA, Mitochondrial / Q000378:metabolism; D028441:F2-Isoprostanes / Q000652:urine; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial; D028441:F2-Isoprostanes; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D000450:Aldosterone; D008315:Malondialdehyde
keywords: aldosterone; mitochondria; mitochondrial transcription factor A; podocytes