Activation of p53 Promotes Renal Injury in Acute Aristolochic Acid Nephropathy

102

101

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.

mentioning

confidence: 99%

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

Yuan¹,

Kim

Westphal³

et al. 2014

102

101

“…[13][14][15][16] p53 was also implicated in kidney injury induced by folic acid, aristolochic acid, and glycerol injection. [17][18][19] As a result, inhibition of p53 may offer an effective therapy for AKI, 12,16,20 and small interfering RNA (siRNA) targeting p53 has been tested for AKI in clinical trials (http://clinicaltrials.gov/ct2/results? term=I5NP&Search=Search).…”

mentioning

confidence: 99%

Tubular p53 Regulates Multiple Genes to Mediate AKI

Zhang

Liu

Wei

et al. 2014

142

163

A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-a, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.

“…[6][7][8][9][10][11] This transcription factor primarily responds to cellular stress and DNA damage by halting the cell cycle and by promoting apoptosis in extreme cases of cell stress. 12,13 Whereas the primary role of p53 activation is to safeguard the genome and prevent malignant transformation, its role in AKI is less straightforward and can be detrimental inasmuch as it can trigger cell death in sublethally injured tubular cells.…”

mentioning

confidence: 99%

p53 Is Renoprotective after Ischemic Kidney Injury by Reducing Inflammation

Sutton

Hato

Mai

et al. 2013

In the rat, p53 promotes tubular apoptosis after ischemic AKI. Acute pharmacologic inhibition of p53 is protective in this setting, but chronic inhibition enhances fibrosis, demonstrating that the role of p53 in ischemic AKI is incompletely understood. Here, we investigated whether genetic absence of p53 is also protective in ischemic AKI. Surprisingly, p53-knockout mice (p53 2/2 ) had worse kidney injury, compared with wild-type mice, and exhibited increased and prolonged infiltration of leukocytes after ischemia. Acute inhibition of p53 with pifithrin-a in wild-type mice mimicked the observations in p53 2/2 mice. Chimeric mice that lacked p53 in leukocytes sustained injury similar to p53 2/2 mice, suggesting an important role for leukocyte p53 in ischemic AKI. Compared with wild-type mice, a smaller proportion of macrophages in the kidneys of p53 2/2 and pifithrin-a-treated mice after ischemic injury were the anti-inflammatory M2 phenotype. Ischemic kidneys of p53 2/2 and pifithrin-a-treated mice also showed reduced expression of Kruppel-like factor-4. Finally, models of peritonitis in p53 2/2 and pifithrin-a-treated mice confirmed the anti-inflammatory role of p53 and its effect on the polarization of macrophage phenotype. In summary, in contrast to the rat, inflammation characterizes ischemic AKI in mice; leukocyte p53 is protective by reducing the extent and duration of this inflammation and by promoting the anti-inflammatory M2 macrophage phenotype. Human AKI is a grave clinical condition frequently seen in the setting of nephrotoxic insults, sepsis, and hemodynamic compromise. Despite decades of clinical and laboratory studies, there are no established therapeutic modalities that are known to alter the course of AKI. Consequently, treatment for AKI to date is supportive and focused on the maintenance of body homeostasis through the control of fluids and electrolytes with modalities as aggressive as dialysis. 1,2 In addition, human AKI unfortunately carries significant morbidity and mortality and can frequently result in long-term loss of function, especially when superimposed on preexisting kidney disease. [3][4][5] Renal artery or pedicle clamp models of ischemiareperfusion injury (IRI) in mice and rats have primarily been utilized to study the pathophysiologic pathways involved in ischemic AKI. The emerging picture of this pathophysiology is that of a complex and often interrelated array of signaling events triggered primarily by hypoxia, reactive oxygen and nitrogen species, and nucleotide depletion. These triggering events in turn can activate or suppress a myriad of secondary effectors such as transcription factors, chemokines, and cytokines. 1 The ultimate result is tubular cell death in the form of apoptosis and necrosis, endothelial alterations, and infiltration of inflammatory cells. The final phenotype of AKI is likely dependent on the particular injury model used and possibly the animal species under investigation.