Deficit of p66ShcA restores redox-sensitive stress response program in cisplatin-induced acute kidney injury

Abstract

Overwhelming oxidative stress and compromised tubular cell antioxidant response have been incriminated for cisplatin (Cis) -induced acute kidney injury (AKI). We hypothesized that Cis-induced KI was the outcome of the deactivated redox-sensitive stress response program (RSSRP). Wild (WT) and heterozygous p66ShcA+/− mice in groups of six were administered either normal saline (WT) or Cis (12.5 mg/kg, intraperitoneal, Cis/WT). Renal biomarkers were collected and kidneys were harvested for renal histology. Cis/WT showed elevated blood urea nitrogen levels and enhanced tubular cell apoptosis, necrosis, and dilated tubules filled with casts when compared to Cis/p66+/−. Cis/p66+/− developed only a clinically occult ARF (normal blood urea levels and only microscopic alterations). Immunoblots from the lysates of renal tissues of Cis/WT displayed enhanced expression of phospho-p66ShcA, and phospho-Foxo3A but attenuated expression of MnSOD and catalase; conversely, p66 deficit prevented these alterations in Cis milieu. In in vitro studies, Cis treated mouse proximal tubular cells (MPTCs) displayed enhanced phosphorylation of p66ShcA and no increase in tubular cell expression of MnSOD. In addition, renal tissues of Cis/WT and Cis-treated MPTCs displayed enhanced phosphorylation of p53 and Bax expression. However, MPTC partially silenced for p66ShcA displayed partial inhibition of Cis-induced tubular cell apoptosis as well as necrosis. These findings indicated that Cis-induced AKI was the outcome of the deactivated RSSRP (attenuated anti-oxidant response) and activation of pro-apoptotic (p53-induced Bax expression) pathway.

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

“…Oxidative stress and mitochondrial dysfunction related to ATP depletion have been observed in response to cisplatin-induced cellular injury in the kidney ( Arany and Safirstein, 2003 ). Rattanavich et al (2013) reported that cisplatin treatment results in diminished expression of renal Mn-SOD via the enhanced expression of phospho-p66ShcA and phospho-Foxo3A in studies featuring heterozygous p66ShcA ( ± ) mice. Specifically, increased expression of phospho-p66ShcA and phospho-Foxo3A was detected in the renal tissue of wild-type mice treated with cisplatin in association with reduced expression of both Mn-SOD and catalase.…”

Renal Protective Effect of Sirtuin 1

“…The main side effect of cisplatin is AKI, with an incidence rate of 25% to 35%. Recent studies have shown that cisplatin-related AKI is caused by attenuated antioxidant effects [ 26 ]. Jung et al [ 27 ] found that SIRT1 can attenuate the mediated nephrotoxicity of platinum compounds.…”

Forskolin Modulate Silent Information Regulator 1 (SIRT1) gene Expression and Halts Experimentally-Induced Acute Kidney Injury

“…First mechanism, SIRT1 up-regulation can degrade excessive free radicals, so increase purine degradation, and lead to ATP generation thus can ameliorate AKI by inhibition of oxidative stress and the another mechanism, SIRT1 by up-regulating the number and function of mitochondria that have a direct effect on cell apoptosis, ATP synthesis, and maintains the normal cell and organ functions. Disturbance in Mitochondrial is an important factor for acute kidney disease that is caused by toxic substances or ischemia [39]. FSK significantly increased the SIRT1 mRNA in kidneys of rats.…”