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Effects of endothelin-3 and leptin in renal morphology and function in vivo: involvement of the intrarenal renin-angiotensin system

Grant number: 13/19569-3
Support type:Regular Research Grants
Duration: July 01, 2014 - December 31, 2016
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Maria Oliveira de Souza
Grantee:Maria Oliveira de Souza
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Introduction: The kidneys are important organs for the biology of the renin-angiotensin system (RAS), endothelin (ET), and leptin. The kidneys synthesize angiotensin II (Ang II) and three active isoforms of ET (ET-1, ET -2 and ET- 3). In addition express Ang II receptors (AT-1 and AT-2), ET receptors (ET- A and ET-B) and leptin receptors (OB -Ra and OB-Rb).Aim: The proposal meeting in this Project Regular have in common the study of renal morphology and function during hypertension associated with the interaction effects of Ang II with endothelin 3 (ET - 3) or leptin. All projects are focused on the study of renal hemodynamics, tubular morphology and function, the mRNA expression of genes for components of the RAS, ET receptors and leptin, the protein expression and identification of factors responsible for injury in renal tissue.Description: In the study of number 1 will be assessed the effect of chronic treatment with Ang II and/or losartan or ABT 627 (AT- receptor antagonists, ET-1 and A respectively); effect of chronic treatment with ET-3 and/or BQ 788 (antagonist of ET-B) on blood pressure, renal morphology, hemodynamics, tubular function and, expression of mRNA for the endothelin system genes (pro-endothelin converting enzyme ETs-ECE1-ECE3) and genes of the SRA (angiotensinogen, renin, and converting enzymes Ang II-ACE and ACE2); expression of ET-A receptors, ET- B, AT-1 and AT-2 in different portions of the kidney. Will be also evaluated the expression of sodium transporters [(exchanger Na+/H+ isoform 3-NHE3; cotransporter Na+/K+/2Cl--NKCC2) and the epithelial Na+ channel-ENaC ± and ² isoforms]. In the study number 2 will be assessed the effect of chronic treatment with leptin and/or losartan on blood pressure, renal hemodynamics, morphology, tubular function and mRNA expression of genes: angiotensinogen, renin, ACE, nephrin (expressed in podocytes and processes involved in albuminuria), the protein expression of leptin receptor Ob -Rb and receptors of angiotensin II (AT-1 and AT-2). Methods employed: Renal function will be assessed by renal clearance experiments and analyzes of plasma and urinary parameters. The morphological analyzes will be performed by immunohistochemical localization of proteins through microscope coupled to a video camera and an image analysis program (Axiovision, Carl Zeiss). The location of the ET-A receptors, ET- B AT-1 and AT-2 in different portions of the kidney will be evaluated by immunofluorescence. Gene expression will be evaluated by RT-PCR (reverse transcription-polymerase chain reaction) and protein expression will be evaluated by Western Blot.Expected Results: These studies will contribute to the clarification of the effects of the interaction between the renin angiotensin and endothelin 3 or hyperleptinemia in the mechanisms involved in the renal tissue injury. The clarification of these processes will allow us in the future, the search for pharmacological treatments appropriate to correct the damage that Ang II and endothelin associated with hyperleptinemia will generate on the kidneys. All morphological and functional changes observed will be the basis for future in vivo studies using endothelin-1 and in vitro, with which we intend to explore the signaling pathways involved in the mechanisms associated with the effects of the interaction between RAS, ETs and hyperleptinemia in glomerular, tubular and podócitária injury. In vitro studies will be conducted in permanent culture of mesangial cells, podocytes, proximal tubules and collecting ducts cells. (AU)

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)
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, DEC 20 2018. Web of Science Citations: 3.
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, SEP 2018. Web of Science Citations: 2.
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, JUL 13 2018. Web of Science Citations: 7.
MALAVAZZI CASARE, FERNANDO AUGUSTO; THIEME, KARINA; COSTA-PESSOA, JULIANA MARTINS; ROSSONI, LUCIANA VENTURINI; COUTO, GISELE KRUGER; FERNANDES, FERNANDA BARRINHA; CASARINI, DULCE ELENA; OLIVEIRA-SOUZA, MARIA. Renovascular remodeling and renal injury after extended angiotensin II infusion. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 310, n. 11, p. F1295-F1307, JUN 1 2016. Web of Science Citations: 11.
MONTEIRO, MARIA BEATRIZ; THIEME, KARINA; SANTOS-BEZERRA, DANIELE PEREIRA; QUEIROZ, MARCIA SILVA; WORONIK, VIKTORIA; PASSARELLI, MARISA; MACHADO, UBIRATAN FABRES; GIANNELLA-NETO, DANIEL; OLIVEIRA-SOUZA, MARIA; CORREA-GIANNELLA, MARIA LUCIA. Beta-2-microglobulin (B2M) expression in the urinary sediment correlates with clinical markers of kidney disease in patients with type 1 diabetes. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 65, n. 6, p. 816-824, JUN 2016. Web of Science Citations: 8.
MONTEIRO, MARIA BEATRIZ; SANTOS-BEZERRA, DANIELE PEREIRA; THIEME, KARINA; ADMONI, SHARON NINA; PEREZ, RICARDO VESSONI; MACHADO, CLEIDE GUIMARAES; QUEIROZ, MARCIA SILVA; NERY, MARCIA; OLIVEIRA-SOUZA, MARIA; WORONIK, VIKTORIA; PASSARELLI, MARISA; GIANNELLA-NETO, DANIEL; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA. Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes. Free Radical Research, v. 50, n. 1, p. 101-110, JAN 2 2016. Web of Science Citations: 9.
THIEME, KARINA; OLIVEIRA-SOUZA, MARIA. Renal Hemodynamic and Morphological Changes after 7 and 28 Days of Leptin Treatment: The Participation of Angiotensin II via the AT(1) Receptor. PLoS One, v. 10, n. 3 MAR 20 2015. Web of Science Citations: 9.

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