Role of TRPM5 in RAAS modulating in diabetic kidney disease in mice with type 2 diabetes mellitus

• Grant number: 25/04271-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Cláudia Silva Souza
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases, AP.TEM

Abstract

Diabetic kidney disease (DKD) is the most common microvascular complication of chronic hyperglycemia and the leading cause of end-stage renal disease (ESRD) worldwide. The renin-angiotensin-aldosterone system (RAAS) plays a central role in hemodynamic alterations, serving as the primary trigger of kidney damage in chronic kidney disease (CKD). Consequently, RAAS inhibitors and blockers are the most widely used pharmacological interventions. However, these therapies alone are insufficient to halt or reverse CKD progression to ESRD. Emerging evidence suggests that transient receptor potential melastatin 5 (TRPM5) may be involved in RAAS modulation and ESRD development. However, the precise mechanisms by which this ion channel contributes to these processes remain poorly understood. Here we hypothesize that the absence of TRPM5 in the final portion of the TCD is related to a lower influx of Na+ in this segment of the nephron, interfering with the transepithelial electrical potential difference and K+ secretion, thus contributing to hyperkalemia in DKD, per se, and when in dual inhibition of the RAAS. This project aims to identify and characterize the role of TRPM5 in DKD, investigating whether its absence affects distal sodium absorption, RAAS activation, and hyperkalemia particularly in the context of dual RAAS inhibition in DKD. To achieve this, the study will employ in vivo models of type 2 diabetes mellitus (T2DM) using wild-type and TRPM5-knockout animals, treated or untreated with angiotensin receptor blockers (ARBs) and mineralocorticoid receptor inhibitors (MRIs). Additionally, in vitro experiments will utilize a co-culture system of distal convoluted tubule cells and podocytes exposed to high glucose conditions and stimulated with TRPM5 activators, ARBs and MRIs. By elucidating the mechanisms through which TRPM5 contributes to DKD via RAAS modulation, this study will generate new insights into DKD pathophysiology and potentially uncover a novel therapeutic target for its treatment.