Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice

Jonathan M. Fonseca, Ana P. Bastos, Andressa G. Amaral, Mauri F. Sousa, Leandro E. Souza, Denise M. Malheiros, Klaus Piontek, Maria C. Irigoyen, Terry J. Watnick, Luiz F. Onuchic

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

We have bred a Pkd1 floxed allele with a nestin-Cre expressing line to generate cystic mice with preserved glomerular filtration rate to address the pathogenesis of complex autosomal dominant polycystic kidney disease (ADPKD) phenotypes. Hypertension affects about 60% of these patients before loss of renal function, leading to significant morbimortality. Cystic mice were hypertensive at 5 and 13 weeks of age, a phenotype not seen in noncystic controls and Pkd1-haploinsufficient animals that do not develop renal cysts. Fractional sodium excretion was reduced in cystic mice at these ages. Angiotensinogen gene expression was higher in cystic than noncystic kidneys at 18 weeks, while ACE and the AT1 receptor were expressed in renal cyst epithelia. Cystic animals displayed increased renal cAMP, cell proliferation, and apoptosis. At 24 weeks, mean arterial pressure and fractional sodium excretion did not significantly differ between the cystic and noncystic groups, whereas cardiac mass increased in cystic mice. Renal concentrating deficit is also an early finding in ADPKD. Maximum urine osmolality and urine nitrite excretion were reduced in 10-13- and 24-week-old cystic mice, deficits not found in haploinsufficient and noncystic controls. A trend of higher plasma vasopressin was observed in cystic mice. Thus, cyst growth most probably plays a central role in early-stage ADPKD-associated hypertension, with activation of the intrarenal renin-angiotensin system as a key mechanism. Cyst expansion is also likely essential for the development of the concentrating deficit in this disease. Our findings are consistent with areas of reduced perfusion in the kidneys of patients with ADPKD.

Original languageEnglish (US)
Pages (from-to)1137-1150
Number of pages14
JournalKidney international
Volume85
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • Cystic kidney
  • Hypertension
  • Nitric oxide
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Nephrology

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