Research Grants 17/02020-0 - Insuficiência renal crônica, Lesão renal aguda - BV FAPESP
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Mechanisms involved in the transition from post-ischemic acute kidney injury to chronic kidney disease: contribution of angiotensin II and albumin

Abstract

Chronic kidney disease (CKD) is a public health problem characterized by high morbidity and mortality and with important social and economic impact on the health system. Acute kidney injury (AKI) secondary to the ischemia and reperfusion process is a common condition for the progression of CKD associated with increased renin-angiotensin system activity, inflammation, fibrosis and decrease of renal function. Furthermore, in the progression of CKD, albuminuria associated with glomerular basement membrane (MBG) lesions, podocyte effacement and tubular injury, becomes an important indicator for kidney failure. However, the pathophysiological and tissue repair mechanisms associated with the transition from AKI to CKD, as well as the cellular mechanisms involved in the action of albumin on podocytes are poorly understood. The current study, which consists of two subprojects, aims to investigate the mechanisms responsible for the transition from post-ischemic AKI to CKD, as well as the contribution of angiotensin II (Ang II) via AT1 receptor and PPAR³ (peroxisome proliferator- Activated receptor gamma) respectively, in renal tissue injury and repair. In addition, will be investigate the mechanisms by which albumin contributes to podocyte injury. Methods: In the first subproject, the transition from AKI to CKD will be investigated in C57BL/6J mice, organized into five groups: 1) control, 2) with sham surgery; 3) with ischemia of 45 minutes by renal artery occlusion, followed by reperfusion; 4) ischemia/reperfusion and treated with telmisartan (AT 1 receptor antagonist); 5) ischemia/reperfusion, treated with telmisartan and GW9662 (PPAR³ inhibitor). Renal injury progression will be assessed at 48 hours, 4, 14 and 28 days after renal ischemia and reperfusion. This study will investigate the contribution of Ang II, PPAR³ and NADPH oxidase enzymes in the synthesis of factors associated with endoplasmic reticulum stress, inflammatory, fibrotic and apoptotic factors, as well as renal tissue repair factors. In the second subproject, the contribution of megalin/cubilin receptors to albumin endocytosis and the effect of intracellular albumin on podocyte injury will be investigated, considering the participation of NADPH oxidase enzymes and endoplasmic reticulum stress. The methodologies applied consist of assessment of tail pressure by plethysmography, creatinine clearance, plasma hormone concentrations evaluation, hydroelectrolytic measurements by flame photometry and osmometer, quantitative PCR (qPCR) to evaluate mRNA expression, Western blotting, to evaluate Protein expression, immunohistochemistry and immunofluorescence to evaluate the protein distribution in different portions of the renal tissue. Statistical analysis of the data will be performed by one-way or two-way ANOVA, completely randomized, followed by the Bonferroni post-hoc test, performed using the GraphPad Prism Software program. Values of p <0.05 will be considered statistically significant and the results will be presented as an average value ± standard error. (AU)

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Scientific publications (7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LEITE-DELLOVA, DEISE C. A.; SZRIBER, SHIRLEY J.; MERIGHE, GIOVANA K. F.; POLIDORO, JULIANO Z.; REBOUCAS, NANCY A.; OLIVEIRA-SOUZA, MARIA; DE MELLO-AIRES, MARGARIDA. Signaling pathways involved in the rapid biphasic effect of aldosterone on Na+/H(+)exchanger in rat proximal tubule cells. JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, v. 182, p. 87-94, . (11/19967-3, 17/02020-0, 13/19569-3, 13/23087-4)
CARDOSO, VANESSA GEROLDE; GONCALVES, GUILHERME LOPES; COSTA-PESSOA, JULIANA MARTINS; THIEME, KARINA; LINS, BRUNA BEZERRA; MALAVAZZI CASARE, FERNANDO AUGUSTO; DE PONTE, MARIANA CHARLEAUX; SARAIVA CAMARA, NIELS OLSEN; OLIVEIRA-SOUZA, MARIA. Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-delta/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity. BMC Nephrology, v. 19, . (14/19154-0, 13/23087-4, 13/19569-3, 11/14022-0, 14/17251-9, 17/02020-0)
CARDOSO, VANESSA GEROLDE; DE PONTE, MARIANA CHARLEAUX; DE SOUZA, MARIA OLIVEIRA. The Role of Obesity in the Development of Kidney and Glomerular Ultrafiltration Barrier Injuries: Leptin Contributions. FASEB JOURNAL, v. 35, p. 2-pg., . (17/02020-0)
DE ARAUJO, LARISSA; COSTA-PESSOA, JULIANA MARTINS; DE PONTE, MARIANA CHARLEAUX; OLIVEIRA-SOUZA, MARIA. Sodium Oxalate-Induced Acute Kidney Injury Associated With Glomerular and Tubulointerstitial Damage in Rats. FRONTIERS IN PHYSIOLOGY, v. 11, p. 12-pg., . (16/12354-0, 17/02020-0, 19/06358-0)
GONCALVES, GUILHERME LOPES; COSTA-PESSOA, JULIANA MARTINS; THIEME, KARINA; LINS, BRUNA BEZERRA; OLIVEIRA-SOUZA, MARIA. Intracellular albumin overload elicits endoplasmic reticulum stress and PKC-delta/p38 MAPK pathway activation to induce podocyte apoptosis. SCIENTIFIC REPORTS, v. 8, . (17/02020-0, 14/17251-9, 13/19569-3, 13/23087-4)
LINS, BRUNA BEZERRA; CASARE, FERNANDO AUGUSTO MALAVAZZI; FONTENELE, FLAVIA FERREIRA; GONCALVES, GUILHERME LOPES; OLIVEIRA-SOUZA, MARIA. Long-Term Angiotensin II Infusion Induces Oxidative and Endoplasmic Reticulum Stress and Modulates Na+ Transporters Through the Nephron. FRONTIERS IN PHYSIOLOGY, v. 12, . (18/26528-5, 17/02020-0, 13/23087-4, 19/13584-7)
DE PONTE, MARIANA CHARLEAUX; CARDOSO, VANESSA GEROLDE; GONCALVES, GUILHERME LOPES; COSTA-PESSOA, JULIANA MARTINS; OLIVEIRA-SOUZA, MARIA. Early type 1 diabetes aggravates renal ischemia/reperfusion-induced acute kidney injury. SCIENTIFIC REPORTS, v. 11, n. 1, . (17/02020-0, 16/12354-0, 18/26528-5, 19/13584-7)

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