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.
Highlights
Chronic kidney disease (CKD) is a major public health problem that imposes enormous socioeconomic burdens on patients, families and societies
Some mitochondria exhibited disrupted membranes and the complete loss of cristae compared to normal mitochondria in the sham group
We used rotenone to damage HK2 cells and induce apoptosis, and similar mitochondrial changes were observed after incubation with the mitochondrial respiratory chain complex inhibitor (Figure 2 B)
Summary
Chronic kidney disease (CKD) is a major public health problem that imposes enormous socioeconomic burdens on patients, families and societies. Tubulointerstitial fibrosis, is a common final outcome of most progressive CKD [1]. Major cellular events in tubulointerstitial fibrosis include inflammatory cell infiltration, fibroblast activation, the loss of peritubular capillaries and tubular atrophy [2]. Mitochondria are energy-producing organelles that perform key cellular tasks. A deregulation of the mitochondrial respiratory machinery was observed in patients with CKD [3]. The structural characteristics of CKD may be partially due to the gradual loss of renal energy through the development of mitochondrial dysfunction. Dysfunctional mitochondria contribute to the pathophysiology of renal disease [4].
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