title: Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice.
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.
authors.affiliation: Divisions of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Fonseca
authors.affiliation: Divisions of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Bastos
authors.affiliation: Divisions of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Andressa G
authors.initials: AG
authors.lastname: Amaral
authors.affiliation: Department of Medicine, Federal University of Goiás School of Medicine, Goiânia, Brazil.
authors.forename: Mauri F
authors.initials: MF
authors.lastname: Sousa
authors.affiliation: Department of Cardiopneumology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Leandro E
authors.initials: LE
authors.lastname: Souza
authors.affiliation: Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Malheiros
authors.affiliation: Department of Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Piontek
authors.affiliation: Department of Cardiopneumology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Irigoyen
authors.affiliation: Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Watnick
authors.affiliation: 1] Divisions of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil [2] Center for Cellular and Molecular Studies and Therapy (NETCEM), University of São Paulo, São Paulo, Brazil.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Onuchic
mesh_terms: D000818:Animals; D017209:Apoptosis; D062186:Arterial Pressure / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000652:urine; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D005838:Genotype; D005919:Glomerular Filtration Rate; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007671:Kidney Concentrating Ability / Q000235:genetics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012084:Renin-Angiotensin System; D050396:TRPP Cation Channels / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: D015415:Biomarkers; D050396:TRPP Cation Channels