title: Hyperglycemia, p53, and mitochondrial pathway of apoptosis are involved in the susceptibility of diabetic models to ischemic acute kidney injury.
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.
authors: 1] Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA [2] Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, China [3] Department of Nephrology, Zhongnan Hospital, Wuhan University, Wuhan, China.
authors: Jianping
authors: J
authors: Peng
authors: 1] Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA [2] Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, China [3] Department of Nephrology, Zhongnan Hospital, Wuhan University, Wuhan, China.
authors: Xiaoning
authors: X
authors: Li
authors: 1] Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA [2] Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China [3] Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Dongshan
authors: D
authors: Zhang
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
authors: Jian-Kang
authors: JK
authors: Chen
authors: Department of Pharmacology and Toxicology, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
authors: Yunchao
authors: Y
authors: Su
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
authors: Sylvia B
authors: SB
authors: Smith
authors: 1] Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA [2] Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors: Zheng
authors: Z
authors: Dong
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000209:etiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006943:Hyperglycemia / Q000150:complications*; D007511:Ischemia / Q000150:complications / Q000209:etiology*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D016159:Tumor Suppressor Protein p53
chemical_list: D016159:Tumor Suppressor Protein p53