title: 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 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 (12.5 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 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.
authors.affiliation: Department of Medicine, Hofstra North Shore LIJ Medical School, New York, United States.
authors.forename: Rungwasee
authors.initials: R
authors.lastname: Rattanavich
authors.forename: Andrei
authors.initials: A
authors.lastname: Plagov
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.forename: Divya
authors.initials: D
authors.lastname: Salhan
authors.forename: Himanshu
authors.initials: H
authors.lastname: Vashistha
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Meggs
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D020868:Gene Silencing; D006579:Heterozygote; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000139:chemically induced; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism*; D010766:Phosphorylation; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494827:Bax protein, mouse; D055765:Shc Signaling Adaptor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D010088:Oxidoreductases; D002945:Cisplatin