Balance between kinin B1 and B2 receptors in the development of tubulointerstitial fibrosis

• Grant number: 20/15895-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): October 01, 2024
• Effective date (End): September 30, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Ronaldo de Carvalho Araújo
• Grantee: Gabriel Rufino Estrela
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Chronic kidney disease represents a significant public health problem. At the histological level, tubulointerstitial fibrosis is the common final consequence of the progression of kidney disease, regardless of the initial insult. Evidence shows that renal inflammation plays a central role both in the initiation and the progression of chronic kidney disease. Some of the inflammatory molecules involved are: MCP-1 (monocyte chemotactic protein-1), kinin B1 receptor (B1R), nuclear factor ºB (NF-ºB), tumor necrosis factor-± (TNF±) and transformation factor of ² growth (TGF-²). In addition to these, some other molecules present with low levels in chronic kidney disease, such as: interleukin-10 (IL-10), interferon-³ (IFN-³), bone morphogenetic protein-7 (BMP-7), hepatocyte growth (HGF). Therefore, the restoration of the balance between the pro and anti-fibrotic factors can lead to an improvement in the tubulo-interstitial fibrosis. Macrophages play an important role in inflammation as well as tissue healing. Many studies show that the profile switch of M1 macrophages (pro-inflammatory) to an M2 profile (anti-inflammatory) attenuates or even prevents the progression of kidney disease. The great importance of kinin receptors in the inflammatory response is well established, and their deletion and antagonism are capable of modulating inflammation in several animal models, such as ischemia and renal reperfusion, cisplatin-induced nephrotoxicity, focal and segmental glomerulosclerosis, among others. Considering the importance of kinin receptors in controlling the inflammatory response and that inflammation is an important step in the development of renal fibrosis, we will use animal models of acute insults with transition to chronic kidney disease, in order to verify whether antagonism and deletion of kinin receptors are able to modulate the development of tubulointerstitial fibrosis and the possible mechanisms underlying.