Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function

Hasiyeti Maimaitiyiming, Yanzhang Li, Wenpeng Cui, Xiaopeng Tong, Heather Norman, Xinyu Qi, Shuxia Wang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear, and the renoprotective agents during cisplatin treatment are still lacking. Here, we demonstrated that the expression and activity of cGMP-dependent protein kinase-I (PKG-I) were reduced in cisplatintreated renal tubular cells in vitro as well as in the kidney tissues from cisplatin-treated mice in vivo. Increasing PKG activity by both pharmacological and genetic approaches attenuated cisplatin-induced kidney cell apoptosis in vitro. This was accompanied by decreased Bax/Bcl2 ratio, caspase 3 activity, and cytochrome c release. Cisplatin- induced mitochondria membrane potential loss in the tubular cells was also prevented by increased PKG activity. All of these data suggest a protective effect of PKG on mitochondria function in renal tubular cells. Importantly, increasing PKG activity pharmacologically or genetically diminished cisplatin-induced tubular damage and preserved renal function during cisplatin treatment in vivo. Mitochondria structural and functional damage in the kidney from cisplatin-treated mice was inhibited by increased PKG activity. In addition, increasing PKG activity enhanced ciaplatin-induced cell death in several cancer cell lines. Taken together, these results suggest that increasing PKG activity may be a novel option for renoprotection during cisplatinbased chemotherapy.

Original languageEnglish
Pages (from-to)F881-F890
JournalAmerican Journal of Physiology - Renal Physiology
Volume305
Issue number6
DOIs
StatePublished - Sep 15 2013

Keywords

  • Cisplatin
  • Mitochondria
  • PKG-I
  • Tubular cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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