Please use this identifier to cite or link to this item: https://observatorio.fm.usp.br/handle/OPI/3016
Title: HYPERTENSION REQUIRES RENAL CYST FORMATION AND IS ASSOCIATED WITH INCREASED INTRARENAL EXPRESSION OF RENIN-ANGIOTENSIN SYSTEM COMPONENTS IN PKD1-DEFICIENT MICE
Authors: FONSECA, Jonathan M.BASTOS, Ana P.AMARAL, Andressa G.SOUSA, Mauri F.SOUZA, Leandro E.MALHEIROS, Denise M.PIONTEK, KlausIRIGOYEN, Maria C.WATNICK, Terry J.ONUCHIC, Luiz F.
Citation: NEPHROLOGY DIALYSIS TRANSPLANTATION, v.27, suppl.2, p.46-46, 2012
Abstract: Introduction and Aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease, being responsible for ∼4-5% of end-stage renal disease cases worldwide. Systemic arterial hypertension (SAH) is an early manifestation of this disorder and is detected in more than half of affected individuals before a significant decline in renal function. A current model proposes that activation of the renin-angiotensin system (RAS) is the primary determinant of SAH in ADPKD. This is mainly due to cyst expansion that results in intrarenal ischemia followed by angiotensin II generation. Methods: By combining a Pkd1 floxed allele with a nestin Cre transgene, we have obtained male, adult cystic mice (Pkd1cond/cond:Balcre aka CondCre). These mice were alive at the age of 10-13 weeks with preserved GFR. This model allowed us to investigate the effects of renal cyst growth on blood pressure and RAS activation. Direct measurement of blood pressure and analyses of a series of renal parameters were performed in CondCre mice and compared with littermate controls (Pkd1cond/cond; Cre-) and Pkd1-haploinsufficient mice (Pkd1+/-). The latter two sets of mice do not develop visible renal cysts at the analyzed age range. Results: CondCre mice were hypertensive, displaying higher mean arterial pressure compared with Cre-animals (150.34 + 3.90, n=6 vs 136.10 + 3.44 mmHg, n=6; p<0.01). Pkd1+/- mice were not hypertensive compared to their wild-type littermates (131.03 + 4.36, n=6 vs 127.54 + 2.99 mmHg, n=8, respectively; p=0.10). Our data also revealed lower fractional excretion of Na+(FENa) in CondCre mice compared with Cre- controls (0.60 + 0.06%, n=9 vs 0.74 + 0.09%, n=9; p<0.001). BUN was slightly higher in CondCres compared to Cre-s [26.3 (26.1-27.9), n=9 vs 24.7 (24.5-25.2), n=9; p<0.01] while serum creatinine was slightly lower [0.32 (0.30-0.34) in CondCres, n=9 vs 0.36 (0.35-0.38) in Cre-s, n=9; p<0.01]. No differences in plasma renin and serum aldosterone could be detected between the two groups but a trend for higher plasma vasopressin was observed in CondCres (711.6 + 647.3 pg/mL, n=9 vs 263.0 + 373.5 inCre-s, n=8; p=0.11). Analyses performed using qPCR at 18 weeks of age revealed increased angiotensinogen gene expression in CondCre kidneys compared to Cre-s (1.76 + 0.65 AU, n=9 vs 1.05 + 0.39 AU, n=8; p<0.05) but no differences were seen in renin and angiotensin converting enzyme (ACE) gene expression. Immunohistochemical analyses performed at 15 weeks revealed specific ACE and AT1 receptor (AT1R) staining in cystic epitelia of CondCre kidneys. As expected, immunohistochemical assays for Ki-67 and TUNEL revealed higher cell proliferation and apoptosis rates in kidneys of CondCres when compared with Cre-s [17%(9-35), n=9 vs 5% (1-9), n=8; p<0.05; and 16,6% (14.0-30.2) vs 0.0% (0.0-4.6); p<0.001, respectively]. Conclusions: Our results suggest that SAH in CondCre mice is primarily caused by renal cyst expansion. There are several pieces of data that support this conclusion. First, we observed a decreased FENa along with mildly elevated BUN in CondCre animals, which is consistent with renal vascular compression and decreased renal perfusion. In addition, we detected increased expression of angiotensinogen in cystic kidneys, along with an increase in immunoreactivity for ACE and AT1R in cyst lining epithelia. These findings are consistent with the notion that intrarenal RAS activation plays a critical role in the genesis of hypertension in ADPKD.
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Comunicações em Eventos - FM/MCM
Departamento de Clínica Médica - FM/MCM

Comunicações em Eventos - HC/ICHC
Instituto Central - HC/ICHC

Comunicações em Eventos - HC/InCor
Instituto do Coração - HC/InCor

Comunicações em Eventos - LIM/16
LIM/16 - Laboratório de Fisiopatologia Renal

Comunicações em Eventos - LIM/29
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular

Comunicações em Eventos - LIM/59
LIM/59 - Laboratório de Biologia Celular


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