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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Fonseca, Jonathan M. [1, 2] ; Bastos, Ana P. [1, 2] ; Amaral, Andressa G. [1, 2] ; Sousa, Mauri F. [3] ; Souza, Leandro E. [4] ; Malheiros, Denise M. [5] ; Piontek, Klaus [6] ; Irigoyen, Maria C. [4] ; Watnick, Terry J. [7] ; Onuchic, Luiz F. [1, 2, 8]
Total Authors: 10
Affiliation:
[1] Univ Sao Paulo, Sch Med, Dept Med, Div Nephrol, BR-01246903 Sao Paulo - Brazil
[2] Univ Sao Paulo, Sch Med, Dept Med, Div Mol Med, BR-01246903 Sao Paulo - Brazil
[3] Univ Fed Goias, Sch Med, Dept Med, Goiania, Go - Brazil
[4] Univ Sao Paulo, Sch Med, Inst Heart, Dept Cardiopneumol, BR-01246903 Sao Paulo - Brazil
[5] Univ Sao Paulo, Sch Med, Dept Pathol, BR-01246903 Sao Paulo - Brazil
[6] Univ Maryland, Sch Med, Dept Oncol, Baltimore, MD 21201 - USA
[7] Johns Hopkins Univ, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21205 - USA
[8] Univ Sao Paulo, Ctr Cellular & Mol Studies & Therapy NETCEM, BR-01246903 Sao Paulo - Brazil
Total Affiliations: 8
Document type: Journal article
Source: Kidney International; v. 85, n. 5, p. 1137-1150, MAY 2014.
Web of Science Citations: 16
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 All 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. (AU)

FAPESP's process: 09/10748-7 - Pathogenesis of dysfunctions associates to Pkd1 Gene Deficiency in Mice.
Grantee:Jonathan Mackowiak da Fonseca
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 10/17424-0 - Basis of Arterial Hypertension and Renal Dysfunctions Associated with Autosomal Dominant Polycystic Kidney Disease: Study in Distinct Models of Pkd1 Gene Deficiency in Mice
Grantee:Luiz Fernando Onuchic
Support Opportunities: Regular Research Grants