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: Jun-Feng Chen, Hong Liu, Hai-Feng Ni, Lin-Li Lv, Ming-Hui Zhang, Ai-Hua Zhang, Ri-Ning Tang, Ping-Sheng Chen, Bi-Cheng Liu
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e83593 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24349535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Pyridones
• pirfenidone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Fibrosis (metabolism, pathology, prevention & control)
• Humans
• Kidney Tubules, Proximal (metabolism, pathology)
• Male
• Mitochondria (metabolism, pathology)
• Nephrectomy
• Nephritis, Interstitial (metabolism, pathology, prevention & control)
• Pyridones (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Renal Insufficiency, Chronic (metabolism, pathology, prevention & control)