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Pkd2 dosage influences cellular repair responses following ischemia-reperfusion injury

Prasad, S., McDaid, J.P., Tam, F.W.K., Haylor, J.L. and Ong, A.C.M. (2009) Pkd2 dosage influences cellular repair responses following ischemia-reperfusion injury. American Journal of Pathology, 175 (4). pp. 1493-1503. ISSN 0002-9440

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) results from mutations in either PKD1 or PKD2 and accounts for 10% of all patients on renal replacement therapy. The kidney disease phenotype is primarily characterized by cyst formation, but there are also prominent interstitial changes (inflammation, apoptosis, proliferation, and fibrosis). Using a model of unilateral ischemia-reperfusion injury, we tested the hypothesis that Pkd2 heterozygous kidneys are more sensitive to injury and that this could lead to interstitial inflammation and fibrosis. Baseline tubular proliferation in heterozygous kidneys was twofold higher than in wild-type kidneys. The magnitude and duration of tubular and interstitial proliferative responses was consistently greater in injured heterozygous compared with wild-type kidneys at all time points. Conversely, tubular p21 expression in heterozygotes was lower at baseline and following injury at all time points. Significantly more neutrophils and macrophages were detected in injured Pkd2 heterozygous kidneys at 2 days, correlating with increased expression of the cytokines interleukin (IL)-1 beta and keratinocyte-derived chemokine and resulting in interstitial fibrosis at 28 days. We conclude that Pkd2 dosage influences both susceptibility and nature of the repair responses following injury. Polycystin-2 is therefore likely to play multiple roles in regulating tubular cell viability, repair, and remodeling in the mature kidney.

Item Type: Article
Copyright, Publisher and Additional Information: © 2009 American Society for Investigative Pathology. Reproduced from Am J Pathol 2009, 175:1493-1503 with permission from the American Society for Investigative Pathology.
Keywords: Polycystic Kidney-Disease; CYST formation; Renal injury; Mice; Expression; Haploinsufficiency; Proliferation; Inactivation; Tissue; Genes
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 04 Dec 2009 09:35
Last Modified: 04 Jun 2014 21:41
Published Version: http://dx.doi.org/10.2353/ajpath.2009.090227
Status: Published
Publisher: American Society for Investigative Pathology (ASIP)
Identification Number: 10.2353/ajpath.2009.090227
URI: http://eprints.whiterose.ac.uk/id/eprint/10231

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