Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion

Ana P. Bastos, Klaus Piontek, Ana M. Silva, Dino Martini, Luis F. Menezes, Jonathan M. Fonseca, Ivone I. Fonseca, Gregory G. Germino, Luiz F. Onuchic

Research output: Contribution to journalArticle

Abstract

Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10- to 12-wk-old male noncystic Pkd1+/- and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

Original languageEnglish (US)
Pages (from-to)2389-2402
Number of pages14
JournalJournal of the American Society of Nephrology
Volume20
Issue number11
DOIs
StatePublished - Nov 2009

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Haploinsufficiency
Reperfusion
Ischemia
Kidney
Autosomal Dominant Polycystic Kidney
Heterozygote
Wounds and Injuries
Cell Proliferation
Mutation
Reperfusion Injury
Dilatation
Cell Differentiation
Creatinine
Potassium
Fibrosis
Sodium
Apoptosis
Messenger RNA
Mortality

ASJC Scopus subject areas

  • Nephrology

Cite this

Bastos, A. P., Piontek, K., Silva, A. M., Martini, D., Menezes, L. F., Fonseca, J. M., ... Onuchic, L. F. (2009). Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. Journal of the American Society of Nephrology, 20(11), 2389-2402. https://doi.org/10.1681/ASN.2008040435

Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. / Bastos, Ana P.; Piontek, Klaus; Silva, Ana M.; Martini, Dino; Menezes, Luis F.; Fonseca, Jonathan M.; Fonseca, Ivone I.; Germino, Gregory G.; Onuchic, Luiz F.

In: Journal of the American Society of Nephrology, Vol. 20, No. 11, 11.2009, p. 2389-2402.

Research output: Contribution to journalArticle

Bastos, AP, Piontek, K, Silva, AM, Martini, D, Menezes, LF, Fonseca, JM, Fonseca, II, Germino, GG & Onuchic, LF 2009, 'Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion', Journal of the American Society of Nephrology, vol. 20, no. 11, pp. 2389-2402. https://doi.org/10.1681/ASN.2008040435
Bastos, Ana P. ; Piontek, Klaus ; Silva, Ana M. ; Martini, Dino ; Menezes, Luis F. ; Fonseca, Jonathan M. ; Fonseca, Ivone I. ; Germino, Gregory G. ; Onuchic, Luiz F. / Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. In: Journal of the American Society of Nephrology. 2009 ; Vol. 20, No. 11. pp. 2389-2402.
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AU - Fonseca, Jonathan M.

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