LUCIA DA CONCEICAO ANDRADE
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/12 - Laboratório de Pesquisa Básica em Doenças Renais, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/12 - Laboratório de Pesquisa Básica em Doenças Renais, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Vitamin D Deficiency Aggravates Chronic Kidney Disease Progression after Ischemic Acute Kidney Injury(2014) GONCALVES, Janaina Garcia; BRAGANCA, Ana Carolina de; CANALE, Daniele; SHIMIZU, Maria Heloisa Massola; SANCHES, Talita Rojas; MOYSES, Rosa Maria Affonso; ANDRADE, Lucia; SEGURO, Antonio Carlos; VOLPINI, Rildo AparecidoBackground: Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-beta 1 (TGF-beta 1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD). Methods: Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-beta, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and alpha-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area. Results: IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and alpha-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-beta 1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion: Through inflammatory pathways and involvement of TGF-beta 1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion.
- Vitamin D deficiency aggravates ischemic acute kidney injury in rats(2015) BRAGANCA, Ana Carolina de; VOLPINI, Rildo A.; CANALE, Daniele; GONCALVES, Janaina G.; SHIMIZU, Maria Heloisa M.; SANCHES, Talita R.; SEGURO, Antonio C.; ANDRADE, LuciaVitamin D deficiency (VDD) increases the risk of death in hospitalized patients. Renal ischemia/reperfusion injury (IRI) induces acute kidney injury (AKI), which activates cell cycle inhibitors, including p21, a cyclindependent kinase inhibitor and genomic target of 25-hydroxyvitamin D, which is in turn a potent immunomodulator with antiproliferative effects. In this study, we assess the impact of VDD in renal IRI. Wistar rats were divided into groups, each evaluated for 30 days: control (receiving a standard diet); VDD (receiving a vitamin D-free diet); IRI (receiving a standard diet and subjected to 45-min bilateral renal ischemia on day 28); and VDD + IRI (receiving a vitamin D-free diet and subjected to 45-min bilateral renal ischemia on day 28). At 48 h after IRI, animals were euthanized; blood, urine, and kidney tissue samples were collected. Compared with IRI rats, VDD + IRI rats showed a more severe decrease in glomerular filtration rate, greater urinary protein excretion, a higher kidney/body weight ratio and lower renal aquaporin 2 expression, as well as greater morphological damage, characterized by increased interstitial area and tubular necrosis. Our results suggest that the severity of tubular damage in IRI may be associated with downregulation of vitamin D receptors and p21. VDD increases renal inflammation, cell proliferation and cell injury in ischemic AKI.
- CHRONIC NICOTINE EXPOSURE DOWNREGULATES RENAL KLOTHO EXPRESSION AND TRIGGERS DIFFERENT RENAL AND AUTONOMIC RESPONSES ACCORDING TO THE KLOTHO STATUS IN MICE(2015) COELHO, Fernanda O.; JORGE, Lecticia B.; BRAGANCA, Ana Carolina de; SANCHES, Talita R. C.; CANALE, Daniele; HELOU, Claudia M. B.; IRIGOYEN, Maria Claudia; KUROO, Makoto; ANDRADE, Lucia
- N-acetylcysteine attenuates renal alterations induced by senescence in the rat (vol 48, pg 298, 2013)(2013) SHIMIZU, M. H.; VOLPINI, R. A.; BRAGANCA, A. C. de; CAMPOS, R.; CANALE, D.; SANCHES, T. R.; ANDRADE, L.; SEGURO, A. C.
conferenceObject VITAMIN D DEFICIENCY AGGRAVATES TENOFOVIR INDUCED METABOLIC SYNDROME AND RENAL FAILURE(2013) CANALE, Daniele; BRAGANCA, Ana Carolina de; GONCALVES, Janana; SHIMIZU, Maria Helosa M.; VOLPINI, Rildo A.; ANDRADE, Lucia; SEGURO, Antonio CarlosIntroduction and Aims:Vitamin D deficiency (VDD) is highly prevalent among HIV-infected individuals. Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, has been associated with comorbidities, some of which have been attributed to renal toxicity and metabolic syndrome. The aim of the study was to investigate the effect of VDD on TDF treated rats. Methods:Wistar rats were randomly divided into four groups: control (C, n = 9), receiving a standard diet for 60 days; VDD (n = 6), receiving a free-vitamin D diet for 60 days; TDF (n = 9), receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+TDF (n = 7) received a free-vitamin D diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days. We measured inulin clearance (GFR, mL/min/100g); blood pressure (BP, mmHg), renal blood flow and calculated renal vascular resistance (RVR, mmHg/mL/min); serum levels of 25-hydroxyvitamin D (25(OH)D, ng/mL), cholesterol (mg/dL) and triglycerides (mg/dL); urinary sodium excretion (UVNa,mEq/24h). In renal tissue, we immunoblotted for angiotensin II (AII), endothelial nitric oxide synthase (eNOS) and vitamin D receptor (VDR). Data are expressed as mean ± SEM. Results:Vitamin D levels were similar in C (15.4±1 ng/mL) and TDF (14.8±1.3 ng/mL) groups and <1.5 ng/mL in VDD groups. Body weight, water intake and food ingestion were not different among the 4 groups. Treatment with TDF led to impaired renal function, hypertension, higher RVR and dyslipidemia. Administration of TDF also increased protein expression of AII and VDR. Association of TDF and VDD exacerbates TDF nephrotoxicity, as well as metabolic syndrome. Furthermore, VDD+TDF group showed urinary sodium retention. The increased VDR protein expression in TDF groups may represent a compensatory effect to decrease renal injury. Conclusions:VDD aggravates renovascular effects and TDF-induced renal failure at least in part due to the involvement of renin-angiotensin-aldosterone system. Therefore, the assessment of vitamin D is important in HIV patients receiving TDF.conferenceObject VITAMIN D DEFICIENCY IS ASSOCIATED WITH DOWNREGULATION OF KLOTHO AND DEVELOPMENT OF FIBROSIS IN A MURINE MODEL OF RENAL ISCHEMIA/REPERFUSION INJURY(2013) GONCALVES, Janaina G.; CANALE, Daniele; BRAGANCA, Ana Carolina de; SHIMIZU, Maria Heloisa M.; MOYSES, Rosa Maria A.; ANDRADE, Lucia; SEGURO, Antonio C.; VOLPINI, Rildo A.Introduction and Aims:Vitamin D deficiency (VDD) is highly prevalent in chronic kidney disease (CKD) patients. Ischemia/reperfusion-Acute Kidney Injury (IR-AKI) is considered a risk factor for CKD progression. Previous studies suggests that activation of the renin-angiotensin-aldosterone system (RAAS) and VDD could be involved in reduction of Klotho expression, an early marker of stage 1 CKD. The aim of this study was to investigate the effect of VDD on klotho expression and fibrosis development in a model of IR-AKI. Methods:Male Wistar rats (180-200g) were randomly divided into four groups (n=8 each): control (C) and ischemic (IR) fed a standard diet; VDD and VDD+IR, fed a free-vitamin D diet. On day 28, IR and VDD+IR rats were submitted to 45-minute clamping of both renal arteries. On day 90, we measured inulin clearance (GFR); Mean arterial blood pressure (MAP), renal blood flow (RBF) and calculated renal vascular resistance (RVR). We also measured serum levels of 25-hydroxyvitamin D (25(OH)D, ng/mL) and proteinuria. In renal tissue, we immunoblotted for klotho and performed imunohistochemical assay for collagen IV and fibronectin. We estimated fibrosis by fractional interstitial area (FIA) and fibronectin/collagen IV expression by score ranging from 0 to 4 according to the extension of staining. Data are expressed as mean ± SEM. Table 1. Hemodynamic and biochemical data and fractional interstitial area, Western Blot and Immunohistochemical studies. Results:Vitamin D levels were similar in C (15.4±1) and IR (15±0.6) groups and <1.5 ng/mL in VDD groups. GFR, RBF and RVR were not different among the studied groups. MAP was markedly elevated in VDD, IR and VDD+IR groups, reflecting a possible interaction on RAAS. Also, VDD, IR and VDD+IR groups showed larger areas of fibrosis and higher scores for fibronectin and collagen IV and decreased levels of klotho. Conclusions:The increased proteinuria/fibrosis and fibronectin/collagen IV expression in VDD+IR rats suggests progressive renal injury. Downregulation of klotho expression is a possible marker of chronification. Our study shows a very plausible role of VDD in this pathway as a potential stimulus for fibrosis.- N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation(2012) CAMPOS, Renata; SHIMIZU, Maria Heloisa Massola; VOLPINI, Rildo Aparecido; BRAGANCA, Ana Carolina de; ANDRADE, Lucia; LOPES, Fernanda Degobbi Tenorio Quirino dos Santos; OLIVO, Clarice; CANALE, Daniele; SEGURO, Antonio CarlosCampos R, Shimizu MH, Volpini RA, de Bragan a AC, Andrade L, Lopes FD, Olivo C, Canale D, Seguro AC. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 302: L640-L650, 2012. First published January 20, 2012; doi: 10.1152/ajplung.00097.2011.-Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the alpha-subunit of the epithelial sodium channel (alpha-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, alpha-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.
- N-acetylcysteine attenuates renal alterations induced by senescence in the rat(2013) SHIMIZU, Maria Heloisa M.; VOLPINI, Rildo A.; BRAGANCA, Ana Carolina de; CAMPOS, Renata; CANALE, Daniele; SANCHES, Talita R.; ANDRADE, Lucia; SEGURO, Antonio C.The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) on renal function, as well as on sodium and water transporters, in the kidneys of aged rats. Normal, 8-month-old male Wistar rats were treated (n = 6) or not (n = 6) with NAC (600 mg/L in drinking water) and followed for 16 months. At the end of the follow-up period, we determined inulin clearance, serum thiobarbituric acid reactive substances (TBARS), serum cholesterol, and urinary phosphate excretion. In addition, we performed immunohistochemical staining for p53 and for ED-1-positive cells (macrophages/monocytes), together with Western blotting of kidney tissue for NKCC2, aquaporin 2 (AQP2), urea transporter A1 (UT-A1) and Klotho protein. At baseline, the two groups were similar in terms of creatinine clearance, proteinuria, cholesterol, and TBARS. At the end of the follow-up period, NAC-treated rats presented greater inulin clearance and reduced proteinuria, as well as lower serum cholesterol, serum TBARS, and urinary phosphate excretion, in comparison with untreated rats. In addition, NAC-treated rats showed upregulated expression of NKCC2, AQP2, and UT-A1; elevated Klotho protein expression, low p53 expression, and few ED-1 positive cells. In conclusion, we attribute these beneficial effects of NAC (the significant improvements in inulin clearance and in the expression of NKCC2, AQP2, and UT-A1) to its ability to decrease oxidative stress, inhibit p53 expression, minimize kidney inflammation, and stimulate Klotho expression.
conferenceObject NATURAL TRIGGERING OF P21 PROTEIN UPREGULATION IS INHIBITED IN VITAMIN D-DEPLETED RATS WITH ISCHEMIC ACUTE KIDNEY INJURY(2012) BRAGANCA, Ana Carolina De; CANALE, Daniele; GONCALVES, Janaina Garcia; BRANDAO, Thais Prevital Bastos; SHIMIZU, Maria Heloisa Massola; VOLPINI, Rildo Aparecido; SEGURO, Antonio Carlos; ANDRADE, LuciaIntroduction and Aims: Renal ischemia/reperfusion injury (IRI), a common cause of acute kidney injury (AKI), activates pathways of cell proliferation and cell death. AKI induces normally quiescent renal cells to enter the cell cycle and triggers the induction of cell cycle inhibitors, including the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1), which is protective against AKI. In mice lacking the p21 gene, AKI is more severe and the resulting renal cell death is more widespread. The potent immunomodulatory and antiproliferative properties of 25-hydroxyvitamin D [25 (OH)D] suggest that it plays a role in the pathophysiology of renal and cardiovascular disease. By altering the levels of several key cell cycle regulators and arresting cells in G0/G1, 25(OH)D can control renal inflammation. It is known that p21, which also arrests cells in G1, is a genomic target of 25(OH)D in many cell types. Prior vitamin D deficiency (VDD) is a major predictor of mortality in critically ill patients. Here, we evaluated the effect of VDD in IRI-induced AKI, hypothesizing that VDD decreases p21 expression and would thus be harmful in AKI. Methods: Wistar rats were fed 25(OH)D-depleted or normal diets for 30 days. On day 28, some rats were induced to IRI by 45-min clamping of both renal arteries. We studied four groups: C (control, n = 7); VDD (n = 5); IRI (n = 7); and VDD+IRI (n = 8). At 48 h after IRI, we measured inulin clearance (CIn); proteinuria; serum levels of 25(OH)D, Ca, and P; urinary volume and osmolality; and fractional excretion of phosphate (FEP). Immunoblotting for p21 and aquaporin 2 (AQP2) was performed in kidney tissue. Data are expressed as mean ± SEM. Results: VDD, IRI and VDD+IRI rats showed higher urine output, higher water intake and lower urinary osmolality. Renal function was impaired in IRI rats. AKI was more severe in VDD+IRI rats, as evidenced by proteinuria and lower CIn. p21 expression was higher in IRI rats than in control rats (134 ± 13.7 vs. 100 ± 1.0%; P < 0.05); in IRI rats than in VDD+IRI and VDD rats (134 ± 13.7 vs. 85.5 ± 1.9 and 64.4 ± 1.7%; P < 0.01); and in control rats than in VDD rats (100 ± 1.0 vs. 64.4 ± 1.7%; P < 0.05). In VDD rats, markedly increased urine output and decreased urinary osmolality were accompanied by decreased AQP2 expression (26.2 ± 0.6; P < 0.001 vs. controls), which was also lower in VDD+IRI rats than in IRI rats (25.2 ± 0.8 vs. 49 ± 1.0; P < 0.001). Conclusions: In otherwise healthy individuals with VDD, renal expression of p21 is downregulated more than usual. This appears to prevent the natural triggering of p21 upregulation in AKI, thereby increasing its severity. VDD might also cause tubular dysfunction (urinary concentrating defect). Further studies are needed in order to determine whether the correction of VDD provides clinical benefits in AKI.- Vitamin D Deficiency Aggravates Nephrotoxicity, Hypertension and Dyslipidemia Caused by Tenofovir: Role of Oxidative Stress and Renin-Angiotensin System(2014) CANALE, Daniele; BRAGANCA, Ana Carolina de; GONCALVES, Janaina Garcia; SHIMIZU, Maria Heloisa Massola; SANCHES, Talita Rojas; ANDRADE, Lucia; VOLPINI, Rildo Aparecido; SEGURO, Antonio CarlosVitamin D deficiency (VDD) is prevalent among HIV-infected individuals. Vitamin D has been associated with renal and cardiovascular diseases because of its effects on oxidative stress, lipid metabolism and renin-angiotensin-aldosterone system (RAAS). Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, can induce renal injury. The aim of this study was to investigate the effects of VDD on TDF-induced nephrotoxicity. Wistar rats were divided into four groups: control, receiving a standard diet for 60 days; VDD, receiving a vitamin D-free diet for 60 days; TDF, receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+ TDF receiving a vitamin D-free diet for 60 days with the addition of TDF for the last 30 days. TDF led to impaired renal function, hyperphosphaturia, hypophosphatemia, hypertension and increased renal vascular resistance due to downregulation of the sodium-phosphorus cotransporter and upregulation of angiotensin II and AT1 receptor. TDF also increased oxidative stress, as evidenced by higher TBARS and lower GSH levels, and induced dyslipidemia. Association of TDF and VDD aggravated renovascular effects and TDF-induced nephrotoxicity due to changes in the redox state and involvement of RAAS.