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The role of uromodulin in the pathogenesis of diabetic nephropathy

Grant number: 15/24991-1
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): March 15, 2016
Effective date (End): March 14, 2017
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Roberto Zatz
Grantee:Orestes Foresto Neto
Supervisor: Hans-Joachim Anders
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Ludwig Maximilian University of Munich (LMU Munich), Germany  
Associated to the scholarship:13/12256-0 - The role of innate immunity in pathogenesis of diabetic nephropathy, BP.DD


Diabetic nephropathy (DN) is one of the most important causes of end-stage renal disease around the world. The mechanisms that lead to the development of DN are complex, and despite progress in recent decades, are still far from being fully understood. Inflammation is involved in both the pathogenesis and progression of DN. There is evidence that activation of innate immunity by diabetes can trigger inflammation. Among the possible components of innate immunity involved in this process are toll-like receptors (TLRs), NF-kappaB system and NLRP3 inflammasome. The activation of these pathways results in the production and maturation of proinflammatory cytokines such as interleukin 1 alpha, 1 beta and 18. Partial results obtained in my PhD's program, in streptozotocin-diabetic rats, suggest that activation of innate immunity components in renal tissue, such as TLR4, the NF-kappaB system and Caspase-1, accompany the development of renal lesions in DN. However, we were unable to show the mechanisms responsible for this activation. Uromodulin (UMOD), also known as Tamm-Horsfall protein, is expressed by renal tubular cells lining the thick ascending limb of the loop of Henle and secreted into the urine. UMOD was first described as having immunosuppressive effects inside the tubular compartment, thereby inhibiting inflammation. However, a number of subsequent studies suggested a proinflammatory role of UMOD in the renal interstitium, specifically by activating neutrophils and monocytes. Increased UMOD levels in urine was demonstrated in chronic kidney disease due to different causes, including diabetes. The research group led by Prof. Hans-Joachim Anders reported in vitro that UMOD activates the NLRP3 inflammasome in human monocytes, leading to the release of IL-1 beta and to cell death. This process was dependent upon TLR4/NF-kappaB activation and the presence of IL-1 alpha. They suggested that, when tubular damage exposes the renal interstitium, UMOD becomes an endogenous danger signal that activates innate immunity, promoting inflammation. Little is known about the specific role of UMOD in DN, but it may be that UMOD is one of the activators of innate immunity in DN, triggering a process of renal injury. In proinflammatory M1 macrophages, the NLRP3 inflammasome is activated by several stimuli. By contrast, anti-inflammatory M2 macrophages downregulate Caspase-1 and do not activate the inflammasome/IL-1 beta pathway. As UMOD is a NLRP3 activator in monocytes, it is possible that it plays different roles in different macrophage phenotypes. Our project was performed to test the hypothesis that increased UMOD excretion in tubular lumen, associated with nephron rupture, increase UMOD release into renal interstitium in DN, activating the TLR4/NF-kappaB and the NLRP3 inflammasome pathways in interstitial monocytes, thus leading to IL-1 alpha and IL-1 beta dependent inflammation. (AU)

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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)
ANDERS, HANS-JOACHIM; SUAREZ-ALVAREZ, BEATRIZ; GRIGORESCU, MELISSA; FORESTO-NETO, ORESTES; STEIGER, STEFANIE; DESAI, JYAYSI; MARSCHNER, JULIAN A.; HONARPISHEH, MOHSEN; SHI, CHONGXU; JORDAN, JUTTA; et al. The macrophage phenotype and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury. Kidney International, v. 93, n. 3, p. 656-669, . (15/24991-1)

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