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

Yuan, Ying; Kim, Jinu; Westphal, Sherry; Long, Kelly E.; Padanilam, Babu J.

doi:10.1681/asn.2013121270

Cited by 102 publications

(108 citation statements)

References 47 publications

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“…[11] showed an administration of pifithrin-α in a single dose at 3 and 14 days after unilateral IRI in mice resulted in diminished cell cycle arrest and fibrosis. In a recent report, Yuan et al [20] also showed that the specific deletion of p53 in the proximal tubule cells attenuated cell cycle arrest and prevented kidney fibrosis [20]. Therefore, in our study, significantly elevated levels of p53 and p21 after AKI in CKD mice compared to AKI in control mice is thought to be partially responsible for progression of fibrosis and inadequate recovery of renal function.…”

Section: Discussionsupporting

confidence: 58%

See 1 more Smart Citation

The Impact of Preexisting Chronic Kidney Disease on the Severity and Recovery of Acute Kidney Injury

Lim¹,

Ko²,

Lee³

et al. 2018

Nephron

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Background: Recent observational studies have shown that in chronic kidney disease (CKD) patients, a significantly smaller percentage of patients with an episode of acute kidney injury (AKI) have full recovery of renal function compared to those without CKD. However, precise mechanisms involved in the incomplete repair after AKI with preexisting CKD have not been completely ascertained. Here, we assessed the impact of preexisting CKD on the severity and recovery of AKI in a mouse model of 5/6 nephrectomy. Methods: Male CD-1 mice underwent 5/6 nephrectomy (Nx). Six weeks post surgery, ischemia reperfusion injury (IRI) or a sham operation was performed and functional, histological, and various molecular parameters were compared between them. Results: Serum creatinine level on day 1 after IRI was comparable between control and Nx mice. However, serum creatinine remained significantly higher throughout the recovery phase in Nx mice compared to control mice. mRNA and protein expression of the cell cycle regulatory proteins were persistently elevated in Nx mice and this was associated with significantly increased levels of the G1 cell cycle arrest markers. Treatment with a p53 inhibitor following IRI resulted in not only decreased expression of G1 arrest markers but also decreased fibrosis, suggesting that prolonged epithelial G1 cell cycle arrest might be partially responsible for impaired recovery from superimposed AKI on CKD. Conclusion: Taken together, reduced nephron mass have a negative effect on the repair process that is partially mediated by the disruption of the cell cycle regulation.

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Section: Discussionsupporting

confidence: 58%

“…The existence of a strong association between p53 and fibrosis has been demonstrated previously. Several studies have shown that the prolonged induction of p21 and p53 is detrimental to kidney fibrosis through continued cell cycle arrest and thus blocking p53 results in the release of arrest and prevention of fibrosis [14, 20]. Yang et al .…”

Section: Discussionmentioning

confidence: 99%

The Impact of Preexisting Chronic Kidney Disease on the Severity and Recovery of Acute Kidney Injury

Lim¹,

Ko²,

Lee³

et al. 2018

Nephron

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“…GO enrichment analysis of these targets showed the over-representation of processes associated with the first stages of kidney damage and repair by stem cell administration, such as the cell adhesion molecules and MAPK signaling. 38 Interestingly, the Wnt signaling pathway, 39 ECM remodeling, 40 and the p53 pathway 41 were also present among the significant biologic processes identified (data not shown). These processes are usually associated with relevant stages in the transition from acute to chronic injury, such as vascular failure, interstitial fibrosis, and glomerulosclerosis development.…”

Section: Discussionmentioning

confidence: 97%

“…These processes are usually associated with relevant stages in the transition from acute to chronic injury, such as vascular failure, interstitial fibrosis, and glomerulosclerosis development. [38][39][40][41] By selecting in this set, only genes not reverted in EV-Dsh treatment with respect to AKI, 165 genes resulted as the possible miRNA targets. GO enrichment analysis of these genes showed that EV-Dshtreated mice overexpressed genes associated with processes related with the progression of kidney damage, such as the Wnt pathway, p53 signaling, ECM remodeling, and focal adhesion processes, like the untreated AKI.…”

Section: Discussionmentioning

confidence: 99%

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Collino

Bruno²,

Incarnato

et al. 2015

Journal of the American Society of Nephrology

222

227

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Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cellpromoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.

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“…PTEN regulates p53 protein levels and transcriptional activity through both phosphatase dependent and independent mechanisms. A crucial role of p53 in tubules damaged by ischemia reperfusion has been reported by the authors' group and others, [12][13][14] and a role of p53 in the HIF-1/miR-687/PTEN signaling pathway is an important issue to be pursued.…”

mentioning

confidence: 86%