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

• Published in: Experimental and molecular pathology 2013-06, Vol.94 (3), p.445-452
• Main Authors: Rattanavich, Rungwasee, Plagov, Andrei, Kumar, Dileep, Rai, Partab, Lederman, Rivka, Salhan, Divya, Vashistha, Himanshu, Malhotra, Ashwani, Meggs, Leonard G., Singhal, Pravin C.
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Blood Urea Nitrogen; Cisplatin - toxicity; Cisplatinum; Female; Gene Silencing; Heterozygote; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Male; Mice; Mice, Knockout; Necrosis - chemically induced; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Oxidoreductases - metabolism; p66ShcA; Phosphorylation; Redox-sensitive stress response program; Shc Signaling Adaptor Proteins - deficiency; Shc Signaling Adaptor Proteins - genetics; Shc Signaling Adaptor Proteins - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2013.03.001

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 AKI was the outcome of the deactivated redox-sensitive stress response program (RSSRP). Wild type (WT) and heterozygous p66ShcA(p66+/−) mice in groups of six were administered either normal saline (WT) or Cis (12.5mg/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 AKI (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 indicate that Cis-induced AKI is the outcome of the deactivated RSSRP (attenuated anti-oxidant response) and activation of pro-apoptotic (p53-induced Bax expression) pathway. •Kidney cells display compromised antioxidant response in cis-induced AKI.•Cis deactivated redox-sensitive stress response program (RSSRP) in tubular cells.•P66ShcA deficit in tubular cells restored RSSRP in cis milieu.