Bax and Bak have critical roles in ischemic acute kidney injury in global and proximal tubule–specific knockout mouse models

Wei, Qingqing; Dong, Guie; Chen, Jian Kang; Ramesh, Ganesan; Dong, Zheng

doi:10.1038/ki.2013.68

Cited by 105 publications

(111 citation statements)

References 42 publications

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“…Systemic deletion of Bax enhanced neutrophil infiltration without significant effect on kidney injury. 27 Our data indicate that expression of Bax, Bid, and Siva are induced in ischemic kidneys but attenuated in p53 KO mice. The significance of Bid and Siva expression in IRI was previously reported.…”

Section: Discussionmentioning

confidence: 58%

“…p53 can upregulate the expression of several proapoptotic genes, including Bax, Fas/Apo-1, PERP, Siva, PUMA, and Noxa, under stress situations. 16 Recently, Dong and colleagues, 27 using two Bax-deficient mouse models, found that only conditional Bax deletion specifically from PTs could ameliorate IRI. Systemic deletion of Bax enhanced neutrophil infiltration without significant effect on kidney injury.…”

Section: Discussionmentioning

confidence: 99%

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Targeted Deletion of p53 in the Proximal Tubule Prevents Ischemic Renal Injury

Yuan¹,

Kim

Westphal³

et al. 2014

Journal of the American Society of Nephrology

101

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The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short-and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-a-treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-b and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Targeted Deletion of p53 in the Proximal Tubule Prevents Ischemic Renal Injury

Yuan¹,

Kim

Westphal³

et al. 2014

Journal of the American Society of Nephrology

101

View full text Add to dashboard Cite

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“…28,37 Remarkably, deletion of apoptotic genes specifically from proximal tubules results in marked decreases in apoptosis and protection from both ischemic and nephrotoxic AKI. 38,39 Together, these studies show an important role of tubular cell apoptosis in AKI.…”

Section: Apoptosis-the Classic View Of Regulated Cell Death In the Kimentioning

confidence: 96%

Regulated Cell Death in AKI

Linkermann

Chen

Dong

et al. 2014

Journal of the American Society of Nephrology

Self Cite

456

392

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AKI is pathologically characterized by sublethal and lethal damage of renal tubules. Under these conditions, renal tubular cell death may occur by regulated necrosis (RN) or apoptosis. In the last two decades, tubular apoptosis has been shown in preclinical models and some clinical samples from patients with AKI. Mechanistically, apoptotic cell death in AKI may result from well described extrinsic and intrinsic pathways as well as ER stress. Central converging nodes of these pathways are mitochondria, which become fragmented and sensitized to membrane permeabilization in response to cellular stress, resulting in the release of cell death-inducing factors. Whereas apoptosis is known to be regulated, tubular necrosis was thought to occur by accident until recent work unveiled several RN subroutines, most prominently receptorinteracting protein kinase-dependent necroptosis and RN induced by mitochondrial permeability transition. Additionally, other cell death pathways, like pyroptosis and ferroptosis, may also be of pathophysiologic relevance in AKI. Combination therapy targeting multiple cell-death pathways may, therefore, provide maximal therapeutic benefits.

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“…Mitochondrial dynamics have emerged as an important aspect in AKI cellular injury (46). Mitochondrial fission occurs during stress or cell ischemic injury, leading to enhanced BAX/BAK sensitivity and apoptosis (47)(48)(49). Additionally, there is marked upregulation (50, 51) of apoptotic regulators (p53) (5,52), initiators (caspases) (53)(54)(55), and protective genes (heme oxygenase, refs.…”

Section: Proximal Tubule Cellsmentioning

confidence: 99%