LEANDRO EZIQUIEL DE SOUZA
Índice h a partir de 2011
7
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
3 resultados
Resultados de Busca
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- Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout(2016) BALBO, Bruno E.; AMARAL, Andressa G.; FONSECA, Jonathan M.; CASTRO, Isac de; SALEMI, Vera M.; SOUZA, Leandro E.; SANTOS, Fernando dos; IRIGOYEN, Maria C.; QIAN, Feng; CHAMMAS, Roger; ONUCHIC, Luiz F.Alterations in myocardial wall texture stand out among ADPKD cardiovascular manifestations in hypertensive and normotensive patients. To elucidate their pathogenesis, we analyzed the cardiac phenotype in Pkd1(cond/cond) Nestin(cre) (CYG+) cystic mice exposed to increased blood pressure, at 5 to 6 and 20 to 24 weeks of age, and Pkd1(+/-) (HTG+) noncystic mice at 5-6 and 10-13 weeks. Echocardiographic analyses revealed decreased myocardial deformation and systolic function in CYG+ and HTG+ mice, as well as diastolic dysfunction in older CYG+ mice, compared to their Pkd1(cond/cond) and Pkd1(+/+) controls. Hearts from CYG+ and HTG+ mice presented reduced polycystin-1 expression, increased apoptosis, and mild fibrosis. Since galectin-3 has been associated with heart dysfunction, we studied it as a potential modifier of the ADPKD cardiac phenotype. Double-mutant Pkd1(cond/cond):Nestin(cre);Lgals(3-/-) (CYG-) and Pkd1(+/-);Lgals(3-/-) (HTG-) mice displayed improved cardiac deformability and systolic parameters compared to single -mutants, not differing from the controls. CYG- and HTG- showed decreased apoptosis and fibrosis. Analysis of a severe cystic model (Pkd1(v/v); VVG+) showed that Pkd1(v/v);Lgals(3-/-) (VVG-) mice have longer survival, decreased cardiac apoptosis and improved heart function compared to VVG+. CYG- and VVG- animals showed no difference in renal cystic burden compared to CYG+ and VVG+ mice. Thus, myocardial dysfunction occurs in different Pkdl-deficient models and suppression of galectin-3 expression rescues this phenotype.
- Smoking accelerates renal cystic disease and worsens cardiac phenotype in Pkd1-deficient mice(2021) SOUSA, Marciana V.; AMARAL, Andressa G.; FREITAS, Jessica A.; MURATA, Gilson M.; WATANABE, Elieser H.; BALBO, Bruno E.; TAVARES, Marcelo D.; HORTEGAL, Renato A.; ROCON, Camila; SOUZA, Leandro E.; IRIGOYEN, Maria C.; SALEMI, Vera M.; ONUCHIC, Luiz F.Smoking has been associated with renal disease progression in ADPKD but the underlying deleterious mechanisms and whether it specifically worsens the cardiac phenotype remain unknown. To investigate these matters, Pkd1-deficient cystic mice and noncystic littermates were exposed to smoking from conception to 18 weeks of age and, along with nonexposed controls, were analyzed at 13-18 weeks. Renal cystic index and cyst-lining cell proliferation were higher in cystic mice exposed to smoking than nonexposed cystic animals. Smoking increased serum urea nitrogen in cystic and noncystic mice and independently enhanced tubular cell proliferation and apoptosis. Smoking also increased renal fibrosis, however this effect was much higher in cystic than in noncystic animals. Pkd1 deficiency and smoking showed independent and additive effects on reducing renal levels of glutathione. Systolic function and several cardiac structural parameters were also negatively affected by smoking and the Pkd1-deficient status, following independent and additive patterns. Smoking did not increase, however, cardiac apoptosis or fibrosis in cystic and noncystic mice. Notably, smoking promoted a much higher reduction in body weight in Pkd1-deficient than in noncystic animals. Our findings show that smoking aggravated the renal and cardiac phenotypes of Pkd1-deficient cystic mice, suggesting that similar effects may occur in human ADPKD.
conferenceObject HYPERTENSION REQUIRES RENAL CYST FORMATION AND IS ASSOCIATED WITH INCREASED INTRARENAL EXPRESSION OF RENIN-ANGIOTENSIN SYSTEM COMPONENTS IN PKD1-DEFICIENT MICE(2012) FONSECA, Jonathan M.; BASTOS, Ana P.; AMARAL, Andressa G.; SOUSA, Mauri F.; SOUZA, Leandro E.; MALHEIROS, Denise M.; PIONTEK, Klaus; IRIGOYEN, Maria C.; WATNICK, Terry J.; ONUCHIC, Luiz F.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.