title: Improved mitochondrial function underlies the protective effect of pirfenidone against tubulointerstitial fibrosis in 5/6 nephrectomized rats.
abstract: Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Ι inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells.
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Ni
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Lv
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu, China ; Institute of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Zhang
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Ri-Ning
authors.initials: RN
authors.lastname: Tang
authors.affiliation: Department of Pathology, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Ping-Sheng
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Institute of Nephrology, Zhong da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.
authors.forename: Bi-Cheng
authors.initials: BC
authors.lastname: Liu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone