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Originally published online as doi:10.2353/ajpath.2009.090227 on September 3, 2009

Published online before print September 3, 2009
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(American Journal of Pathology. 2009;175:1493-1503.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090227

Pkd2 Dosage Influences Cellular Repair Responses following Ischemia-Reperfusion Injury

Sony Prasad*, John Patrick McDaid{dagger}, Frederick Wai Keung Tam{dagger}, John Lionel Haylor* and Albert Chee Meng Ong*

From the Kidney Genetics Group,* Academic Unit of Nephrology, Sheffield Kidney Institute, The Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Sheffield; and Imperial College Kidney and Transplant Institute,{dagger} Hammersmith Hospital, Du Cane Road, London, United Kindgom

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)-1β 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.






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Copyright © 2009 by the American Society for Investigative Pathology.