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.

Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study

“…This finding has been linked to mitochondrial deregulation. 5,[43][44][45] The 635 nm wavelength was the only single-modality treatment group, which enhanced mitochondrial activity at 24 h following administration; addition of MSC to each wavelength led to synergistic effects above that of MSC alone, with the 532 nm and MSC combined treatment group demonstrating greatest gains. When examining reduction of apoptosis, all treatment groups significantly reduced apoptosis at 24 h. These results suggest that MSC synergize with laser to enhance the amount of ATP available to the cell and reduce apoptosis after a single dose of laser energy.…”

NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy

“…In the future, experiments using cell-specific (inflammatory cells, renal epithelial cells, or renal fibroblast cells) NLRP3 KO mice may be required to address this question. Mitochondrial dysfunction has been shown to be an early and key event leading to kidney damage (7,22). Mitochondrial dysfunction could be induced by many insults including infection and noninfection factors via release of inflammatory cytokines and excessive ROS (11,12,19,20).…”

ShenKang injection suppresses kidney fibrosis and oxidative stress via transforming growth factor-β/Smad3 signalling pathway in vivo and in vitro

“…Chronic kidney injury was induced by rats receiving 5/6Nx as described before [18]. Briefly, the rats were anaesthetized under 10% chloral hydrate, two thirds of the left kidney was ablated, and the right kidney was removed after 3 days.…”