Pkd2 dosage influences cellular repair responses following ischemia-reperfusion injury.
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)-1beta 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.
Prasad
Sony
S
Kidney Genetics Group, Academic Unit of Nephrology, Sheffield Kidney Institute, The Henry Wellcome Laboratories for Medical Research, University of Sheffield Medical School, Sheffield S10 2RX, UK.
McDaid
John Patrick
JP
Tam
Frederick Wai Keung
FW
Haylor
John Lionel
JL
Ong
Albert Chee Meng
AC
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D018628:Gene Dosage; D006579:Heterozygote; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000473:pathology; D007684:Kidney Tubules / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000201:enzymology / Q000473:pathology; D015427:Reperfusion Injury / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing
D016207:Cytokines; D050396:TRPP Cation Channels