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Effect of inhibition of inflamassoma NLRP3 and via TLR4 / NF-kB in clinical and experimental conditions of heavy proteinuria

Grant number: 18/05817-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2019
Effective date (End): February 28, 2021
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Roberto Zatz
Grantee:Viviane Dias Faustino
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Chronic Kidney Disease (CKD) involves the participation of a series of inflammatory events that culminate with renal interstitial fibrosis even though the process has started exclusively in the glomeruli. One of the major challenges currently encountered by nephrology is to halt the progression of CKD. Proteinuria correlates with the progression of CKD, particularly when caused by glomerulopathies. One of the main hypotheses put forward to explain this consistent correlation between glomerular lesion and interstitial inflammation is that proteins that cross the damaged glomerular barrier and gain the tubular lumen exert a toxic effect on the proximal tubule cells that reabsorb them, synthesizing inflammatory mediators such as cytokines and chemokines. I have recently shown that innate immunity is activated in rats treated with adriamycin (ADR) and in tubular cells exposed to high concentrations of albumin, which may explain the development of interstitial fibrosis in nephropathies characterized by severe proteinuria. Thus, inhibition of innate immunity may constitute a rational strategy to prevent CKD in this context.The present project aims to verify the effect of inhibition of NLRP3 and TLR4 / NF-kB pathways in a proteinuric renal disease model, as well as in cultured tubular cells. To verify the effect of innate immunity inhibition in vivo I will use rats with adriamycin-induced nephropathy, which will be treated with allopurinol (to inhibit NLRP3 inflammation) and / or PDTC (to inhibit the NF-kB system). In in vitro experiments, I will check the direct effect of inhibition of innate immunity on primary culture of tubular cells obtained from adriamycin treated rats, which will be exposed to high albumin and treated concentrations either with allopurinol or with RNAi for TLR4 and / or NLRP3 .In a clinical counterpart to these experimental studies, I will develop a retrospective study involving biopsy material from patients with segmental and focal glomerulosclerosis, minimal lesions disease or membranous glomerulonephritis, seeking to verify if, at the time of biopsy, the inflammassoma NLRP3 and the TLR4 pathway / NF-kB were activated and if this activation would have made it possible to predict the eventual progression of nephropathy, thus acting as a marker of risk. In another protocol I will verify, through electronic records examination, if the use of allopurinol exerts a renoprotective effect in patients with Chronic Renal Disease.