Hyperglycemia, p53, and mitochondrial pathway of apoptosis are involved in The susceptibility of diabetic models to ischemic acute kidney injury

Jianping Peng, Xiaoning Li, Dongshan Zhang, Jian Kang Chen, Yunchao Su, Sylvia B. Smith, Zheng Dong

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Patients with chronic kidney diseases, including diabetic nephropathy, are more susceptible to acute kidney injury (AKI) and have a worse prognosis following AKI. However, The underlying mechanism is unclear. Here we tested whether diabetic mice were more sensitive to AKI and show that renal ischemia-reperfusion induced significantly more severe AKI and higher mortality in The streptozotocin and Akita diabetic mouse models. The severity of AKI in The mice correlated with their blood glucose levels. In vitro, high glucose-conditioned renal proximal tubular cells showed higher apoptosis and caspase activation following ATP depletion and hypoxic injury, accompanied by a heightened mitochondrial accumulation of Bax and release of cytochrome c. In response to injury, both glucose-conditioned renal proximal tubular cells and diabetic kidney tissues showed markedly higher p53 induction. Suppression of p53 diminished The sensitivity of high glucose-conditioned cells to acute injury in vitro. Moreover, blockade of p53 by pifithrin-α, siRNA, or proximal tubule-targeted gene ablation reduced ischemic AKI in diabetic mice. Insulin reduced blood glucose in diabetic mice and largely attenuated their AKI sensitivity. Thus, our results suggest The involvement of hyperglycemia, p53, and The mitochondrial pathway of apoptosis in The susceptibility of diabetic models to AKI.

Original languageEnglish (US)
Pages (from-to)137-150
Number of pages14
JournalKidney International
Volume87
Issue number1
DOIs
StatePublished - Jan 3 2015

Keywords

  • Acute kidney injury
  • diabetic nephropathy
  • high glucose
  • ischemiareperfusion
  • mitochondria
  • p53

ASJC Scopus subject areas

  • Nephrology

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