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Role of hypoxia in the activation of innate immunity in the progression of chronic kidney disease associated with ablation 5/6 renal model

Grant number: 13/26726-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2015
Effective date (End): September 30, 2017
Field of knowledge:Health Sciences - Medicine
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Roberto Zatz
Grantee:Lisienny Campoli Tono Rempel
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/10926-5 - Pathogenesis and treatment of chronic kidney disease: role of innate immunity in glomerular, tubular and interstitial injury, AP.TEM

Abstract

Chronic kidney disease (CKD) involves a series of inflammatory events that induce fibrosis of the renal parenchyma. No one knows why these processes are triggered even in the absence of microbial antigens or other proteins foreign to the body. The discovery of toll-like receptors (TLRs) and inflamassomas, as well as its interaction with the NF-ºB system, can contribute to solve this issue. In progressive nephropathies, it is possible that activation of innate immunity represents the link between non-specific events, such as the stretching of the glomerular wall, and inflammatory processes that lead to glomerulosclerosis and renal fibrosis. Currently, there is a chance that hypoxia plays an important role in CKD. It has been shown that the final common pathway of renal destruction involves not only interstitial fibrosis and tubular atrophy as well as peritubular capillary rarefaction. Studies suggest that interstitial hypoxia related to the regression of thinning and/or arteriolar vasoconstriction is a primary event in the DRC. It is also possible that the anemic states may predispose renal tissue inflammation, and hypoxia leads to a progression of nephropathy through activation of innate immunity, TLRs and having inflamassomas as participants in this process. Thus, the objective of this study is to evaluate whether chronic hypoxia activates innate immunity and whether this has a pathogenic role in the progression of chronic kidney disease. For this purpose, control rats and rats with renal ablation 5/6 (Nx) will be distributed in four experimental groups for sixty days: S (control animals kept under normoxia) S + H (control animals kept under hypoxia - 12% O2); Nx (Nx animals kept under normoxia); Nx + H (Nx animals kept under hypoxia - 12% O2). All groups will receive a diet low in iron in order to prevent compensatory poliglobulia. The animals will have their body weight recorded weekly; blood pressure flow, Ualb/Ucreat relationship and hematocrit will be evaluated monthly. At the end of the study blood sample will be collected, and the kidney will be properly fixed for histomorphometric analysis of glomerular damage and interstitial expansion, and immunohistochemical detection of markers of hypoxia, components of innate immunity, inflammatory mediators and fibrosis. As markers of hypoxia, will be used anti-HIF-1± and anti-HIF-2² antibodies and antiaducts of pimonidazol, which will be quantified and associated with the expression of molecules related to TLRs and other parameters mentioned. To investigate the possible development of renal fibrosis secondary to hypoxia, rat proximal tubular cells will be grown and maintained in at 37ºC/5%CO2 and 12% O2. Subsequently, these cells will be stained with anti-E-cadherin, anti-vimentin and anti-±-actin antibodies to evaluate a possible process of transdifferentiation to myofibroblasts. Moreover, both in vivo and in vitro experiments, PCR-array will be used to detect the activation of genes related to innate immunity, and Western blot to assess the production of specific proteins such as HIF. (AU)

Scientific publications
(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)
TONO REMPEL, LISIENNY CAMPOLI; FAUSTINO, VIVIANE DIAS; FORESTO-NETO, ORESTES; FANELLI, CAMILLA; ALARCON ARIAS, SIMONE COSTA; DA SILVA MOREIRA, GIZELY CRISTINA; NASCIMENTO, THALITA FABIANA; AVILA, VICTOR FERREIRA; COSTA MALHEIROS, DENISE MARIA AVANCINI; SARAIVA CAMARA, NIELS OLSEN; FUJIHARA, CLARICE KAZUE; ZATZ, ROBERTO. Chronic exposure to hypoxia attenuates renal injury and innate immunity activation in the remnant kidney model. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 317, n. 5, p. F1285-F1292, NOV 2019. Web of Science Citations: 0.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
REMPEL, Lisienny Campoli Tono. Role of hypoxia in the activation of innate immunity and in the progression of chronic kidney disease associated with the renal ablation model of 5/6. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina São Paulo.

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