Cyclosporin A aggravates hydrogen peroxide-induced cell death in kidney proximal tubule epithelial cells

Abstract

Cyclosporin A (CsA) does not only exert a toxic effect on kidney parenchymal cells, but also protects them against necrotic cell death by inhibiting opening of mitochondrial permeability transition pore. However, whether CsA plays a role in hydrogen peroxide-induced kidney proximal tubular cell death is currently unclear. In the present study, treatment with CsA further increased apoptosis and necrosis in HK-2 human kidney proximal tubule epithelial cells during exposure to hydrogen peroxide. In addition, hydrogen peroxide-induced p53 activation and BH3 interacting-domain death agonist (BID) expression were higher in CsA-treated cells than those in non-treated cells, whereas hydrogen peroxide-induced activation of mitogenactivated protein kinases including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase and activation of protein kinase B were not significantly altered by treatment with CsA. In oxidant-antioxidant system, reactive oxygen species (ROS) production induced by hydrogen peroxide was further enhanced by treatment with CsA. However, expression levels of antioxidant enzymes including manganese superoxide dismutase, copper/zinc superoxide dismutase, and catalase were not altered by treatment with hydrogen peroxide or CsA. Treatment with CsA further enhanced mitochondrial membrane potential induced by exposure to hydrogen peroxide, although it did not alter endoplasmic reticulum stress based on expression of glucose-regulated protein 78 and 94. Taken together, these data suggest that CsA can aggravate hydrogen peroxide-induced cell death through p53 activation, BID expression, and ROS production.

Mechanism and reversal of drug-induced nephrotoxicity on a chip

“…The pathogenesis of cyclosporine-induced renal injury is thought to be mediated by vasculopathy that restricts blood flow to the kidney (8,10). Cyclosporine has also been shown to interact with cell membranes at low concentration, inducing proximal tubule damage through oxidative stress (11), endoplasmic reticulum stress (12), and autophagy (13). Abnormal microvacuolization is a pathological hallmark of cyclosporine-induced injury, but its mechanistic relevance is unclear (14).…”

Evaluation of renoprotective effect of grape seed proanthocyanidin extract on Cyclosporine A- induced Nephrotoxicity by mitigating inflammatory response, oxidative stress and apoptosis in rats

“…These mediators increased transforming growth factor-β1 (TGF-β1) expression and plasminogen activator inhibitor-1 (PAI-1) which led to disruption of tissue architecture by increasing extracellular matrix synthesis and decreasing its degradation, resulting in fibrosis of tubule-interstitial and arteriolopathy (Young et al, 1995 (Xiao et al, 2013). The significant up-regulation in kidney tissue p53 gene expression in CsA treated rats came in accordance with (Moon and Kim, 2019). Activation of p53 induced a series of programs, including cell-arrest, cellular senescence and apoptosis (Hsin et al, 2006).…”

The Effect of Polyphenols on Kidney Disease: Targeting Mitochondria

“…ROS production during H 2 O 2 injury could activate the p53 pathway. In addition to binding DNA, activated p53 could accumulate in the mitochondrial matrix and trigger necrotic cell death by opening the MPT pore [ 104 ].…”