DENISE MARIA AVANCINI COSTA MALHEIROS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
4 resultados
Resultados de Busca
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- A Novel Aldosterone Antagonist Limits Renal Injury in 5/6 Nephrectomy(2017) FUJIHARA, Clarice K.; KOWALA, M. C.; BREYER, M. D.; SENA, Claudia R.; RODRIGUES, Mariliza V.; ARIAS, Simone C. A.; FANELLI, Camilla; MALHEIROS, Denise M.; JADHAV, P. K.; MONTROSE-RAFIZADEH, Chahrzad; KRIEGER, Jose E.; ZATZ, RobertoAldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.
- Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1-deficient mice(2014) 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.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.
- Female Patient with Alport Syndrome and Concomitant Membranous Nephropathy: Susceptibility or Association of Two Diseases?(2017) VELOSO, Mariana P.; NEVES, Precil D. M. M.; JORGE, Lecticia B.; DIAS, Cristiane B.; YU, Luis; PINHEIRO, Rafaela B. B.; TESTAGROSSA, Leonardo A.; MALHEIROS, Denise M.; BALBO, Bruno E. P.; LERARIO, Antonio M.; ONUCHIC, Luiz F.; WORONIK, ViktoriaAlport syndrome (AS) is a disorder of collagen IV, a component of glomerular basement membrane (GBM). The association of AS and immunocomplex nephropathies is uncommon. This is a case of a 37-year-old woman with family history of X-linked AS, including 4 affected sons. This patient developed full-blown nephrotic syndrome along a 3-month period, a presentation not consistent with AS progression. This scenario suggested an alternative diagnosis. A kidney biopsy was therefore performed, showing membranous nephropathy (MN) in addition to GBM structural alterations compatible with AS. Whole exome sequencing also confirmed the diagnosis of X-linked AS, revealing a heterozygous pathogenic mutation in COL4A5. While a negative serum anti-phospholipase A2 receptor did not rule out a primary form of MN, it was also uncertain whether positive serologic tests for syphilis could represent a secondary factor. It is currently unknown whether this unusual association represents AS susceptibility to immunocomplex-mediated diseases or simply an association of 2 disorders. (C) 2017 S. Karger AG, Basel
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.