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Hyperglycemia, p53, and mitochondrial pathway of apoptosis are involved in the
susceptibility of diabetic models to ischemic acute kidney injury
#MMPMID24963915
Peng J
; Li X
; Zhang D
; Chen JK
; Su Y
; Smith SB
; Dong Z
Kidney Int
2015[Jan]; 87
(1
): 137-50
PMID24963915
show ga
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-?, 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.
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