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
15 resultados
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- Apolipoprotein A-I mimetic peptide 4F attenuates kidney injury, heart injury, and endothelial dysfunction in sepsis(2014) MOREIRA, Roberto S.; IRIGOYEN, Maria; SANCHES, Talita R.; VOLPINI, Rildo A.; CAMARA, Niels O. S.; MALHEIROS, Denise M.; SHIMIZU, Maria H. M.; SEGURO, Antonio C.; ANDRADE, LuciaKidney injury, heart injury, and cytokine-induced vascular hyperpermeability are associated with high rates of morbidity and mortality in sepsis. Although the mechanism remains unknown, apolipoprotein A-I (apoA-I) mimetic peptide 4F reduces inflammation and protects HDL levels, which are reduced in sepsis. We hypothesized that 4F also protects kidneys and hearts in a rat model of cecal ligation and puncture (CLP). We divided Wistar rats into groups: sham-operated (control), CLP, and CLP+4F (10 mg/kg body wt ip, 6 h after CLP). At 24 h post-CLP, we evaluated cardiac function, mean arterial pressure (MAP), heart rate (HR), baroreflex sensitivity, total cholesterol, LDL, HDL, serum cytokines, and inulin clearance. We performed immunoblotting for protein regulators of vascular permeability (Slit2 and Robo4) and endothelial nitric oxide synthase (eNOS) in kidney tissue. We evaluated heart mitochondria with electron microscopy. Although there was no difference in MAP, the HR was significantly higher in CLP rats than in control and CLP+4F rats. In CLP+4F rats, baroreflex sensitivity and cardiac function were completely protected from the effects of CLP, as was glomerular filtration; heart mitochondria morphology was improved; sepsis-induced changes in serum cholesterol, LDL, HDL, and apoA-I were less common; all cytokines were lower than in CLP rats; and expression of Slit2, Robo4, and eNOS was completely restored. Administration of 4F inhibits inflammatory responses and strengthens the vascular barrier, protecting kidneys and hearts in an HDL-dependent manner. To determine the extent of the protective effect of 4F, further studies are needed.
- Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis(2014) CORREA-COSTA, Matheus; ANDRADE-OLIVEIRA, Vinicius; BRAGA, Tarcio T.; CASTOLDI, Angela; AGUIAR, Cristhiane F.; ORIGASSA, Clarice S. T.; RODAS, Andrea C. D.; HIYANE, Meire I.; MALHEIROS, Denise M. A. C.; RIOS, Francisco J. O.; JANCAR, Sonia; CAMARA, Niels O. S.Platelet-activating factor (PAF) is a lipid mediator with important pro-inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor beta (TGF-beta) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-beta/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to-mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure.
- Effects of Schizolobium parahyba Extract on Experimental Bothrops Venom-Induced Acute Kidney Injury(2014) MARTINES, Monique Silva; MENDES, Mirian M.; SHIMIZU, Maria H. M.; RODRIGUES, Veridiana Melo; CASTRO, Isac de; FERREIRA FILHO, Sebastiao R.; MALHEIROS, Denise M. A. C.; YU, Luis; BURDMANN, Emmanuel A.Background: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI. Methodology: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score). Principal Findings: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone. Conclusion: SP administered simultaneously with BV, in an approximate 10: 1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR.
- IgA nephropathy and polymyositis: a rare association(2014) BARROS, Thiago Bitar Moraes; SOUZA, Fernando Henrique Carlos de; MALHEIROS, Denise Maria Auancini Costa; LEUY-NETO, Mauricio; SHINJO, Samuel KatsuyukiPolymyositis is a systemic and idiopathic inflammatory myopathy that, besides muscle manifestation, may occur with respiratory involvement, gastrointestinal tract and rarely renal involvement. In this latter, there are only two cases of IgA nephropathy, but both in dermatomyositis. On the other hand, we reported, for the first time, a case of IgA nephropathy in polymyositis.
article 0 Citação(ões) na Scopus Kidney biopsy is mandatory in cases of silent arterial hypertension in scleroderma renal crisis: a case report(2014) KOBAYASHI, C. B. C.; BENTO, R. H.; MALHEIROS, D. M. A. C.; ANDRADE, D.; SEGURO, L. C. P.; SAMPAIO-BARROS, P. D.- 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.
- Alpha-melanocyte stimulating hormone ameliorates disease activity in an induced murine lupus-like model(2014) BOTTE, D. A. C.; NORONHA, I. L.; MALHEIROS, D. M. A. C.; PEIXOTO, T. V.; MELLO, S. B. V. deAlpha-melanocyte stimulating hormone (alpha-MSH) is a neuropeptide exhibiting anti-inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of alpha-MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an alpha-MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the alpha-MSH analogue [Nle4, DPhe7]-alpha-MSH (NDP-MSH) (1 25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti-nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, alpha-smooth muscle actin (alpha-SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin-releasing factor (CRF) and alpha-MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)-6, IL-10, proteinuria and mesangial cell proliferation together with glomerular expression of alpha-SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP-MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP-MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of alpha-SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that alpha-MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.
bookPart Neoplasias do rim - carcinoma de células renais(2014) LEITE, Katia Ramos Moreira; MALHEIROS, Denise Maria Avancini Costa; FRANCO, Marcello Fabiano deconferenceObject EXERCISE AND CALORIE RESTRICTION ATTENUATES CISPLATIN-INDUCED ACUTE KIDNEY INJURY(2014) ESTRELA, Gabriel R.; WASINSKI, Frederick; PEREIRA, Rafael; MALHEIROS, Denise; CAMARA, Niels O. S.; ARAUJO, Ronaldo C.bookPart Nova classificação da glomerulonefrite membranoproliferativa: aplicação clínica e compreensão da patogênse(2014) DIAS, Cristiane Bitencourt; TESTAGROSSA, Leonardo; MALHEIROS, Denise