UNC5B receptor deletion exacerbates tissue injury in response to AKI

Punithavathi Ranganathan, Calpurnia Jayakumar, Sutip Navankasattusas, Dean Y. Li, Il Man Kim, Ganesan Ramesh

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. Weinvestigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B-/flox) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B -/flox/GGT-cre). Mice were subjected to two different models of organ injury: ischemia reperfusion injury of the kidney and cisplatin-induced nephrotoxicity. Both mouse models of UNC5B depletion had normal organ function and histology under basal conditions. After AKI, however, UNC5 B-/flox/GGT-cre mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B-/flox and wild-typemice. shRNA-mediated suppression of UNC5B expression in cultured tubular epithelial cells exacerbated cisplatin-induced cell death in a p53-dependent manner and blunted Akt phosphorylation. Inhibition of PI3 kinase similarly exacerbated cisplatin-induced apoptosis; in contrast, overexpression of UNC5B reduced cisplatin-induced apoptosis in these cells. Taken together, these results show that the netrin-1 receptor UNC5B plays a critical role in cell survival and kidney injury through Akt-mediated inactivation of p53 in response to stress.

Original languageEnglish (US)
Pages (from-to)239-249
Number of pages11
JournalJournal of the American Society of Nephrology
Volume25
Issue number2
DOIs
StatePublished - Feb 1 2014

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Cisplatin
Cell Survival
Apoptosis
Wounds and Injuries
Kidney
Epithelial Cells
Reperfusion Injury
Phosphatidylinositol 3-Kinases
Small Interfering RNA
Histology
Cell Death
Phosphorylation
Inflammation
Genes

ASJC Scopus subject areas

  • Nephrology

Cite this

Ranganathan, P., Jayakumar, C., Navankasattusas, S., Li, D. Y., Kim, I. M., & Ramesh, G. (2014). UNC5B receptor deletion exacerbates tissue injury in response to AKI. Journal of the American Society of Nephrology, 25(2), 239-249. https://doi.org/10.1681/ASN.2013040418

UNC5B receptor deletion exacerbates tissue injury in response to AKI. / Ranganathan, Punithavathi; Jayakumar, Calpurnia; Navankasattusas, Sutip; Li, Dean Y.; Kim, Il Man; Ramesh, Ganesan.

In: Journal of the American Society of Nephrology, Vol. 25, No. 2, 01.02.2014, p. 239-249.

Research output: Contribution to journalArticle

Ranganathan, P, Jayakumar, C, Navankasattusas, S, Li, DY, Kim, IM & Ramesh, G 2014, 'UNC5B receptor deletion exacerbates tissue injury in response to AKI', Journal of the American Society of Nephrology, vol. 25, no. 2, pp. 239-249. https://doi.org/10.1681/ASN.2013040418
Ranganathan P, Jayakumar C, Navankasattusas S, Li DY, Kim IM, Ramesh G. UNC5B receptor deletion exacerbates tissue injury in response to AKI. Journal of the American Society of Nephrology. 2014 Feb 1;25(2):239-249. https://doi.org/10.1681/ASN.2013040418
Ranganathan, Punithavathi ; Jayakumar, Calpurnia ; Navankasattusas, Sutip ; Li, Dean Y. ; Kim, Il Man ; Ramesh, Ganesan. / UNC5B receptor deletion exacerbates tissue injury in response to AKI. In: Journal of the American Society of Nephrology. 2014 ; Vol. 25, No. 2. pp. 239-249.
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