Renal TRPM3 Channels Regulate Blood Pressure via Tubuloglomerular Feedback and Plasma Volume Control.

Abstract

BACKGROUND TRPM3 is a nonselective cation channel activated by heat, osmotic pressure, and neurosteroids. It is highly expressed in sensory neurons, where it integrates thermal, chemical, and inflammatory signals to modulate downstream responses, but is also present in the brain, kidney, and cardiovascular system. This distribution suggests a role in cardiovascular and renal regulation. We hypothesize that TRPM3 channels may play a role in blood pressure (BP) regulation via both vascular and renal mechanisms. Therefore, analysis of the vascular phenotype in Trpm3-KO mice can provide insights into the channel's potential contribution to hypertension development. METHODS BP was monitored noninvasively in conscious wild-type and Trpm3-KO mice under basal conditions and after oral losartan treatment or angiotensin II infusion via osmotic minipumps. TRPM3 expression in vessels and kidney structures was examined using immunofluorescence microscopy and RNAscope with specific cell markers. Ex vivo renal perfusion and pressure myography were used to evaluate vascular responses. RESULTS Trpm3-KO mice showed a ≈5% BP reduction and resistance to angiotensin II-induced hypertension. Urine [Na⁺] was 35% to 50% higher, and plasma volume was 20% lower, suggesting a renal origin of the hypotension. TRPM3 was localized at the juxtaglomerular apparatus and distal nephron segments involved in plasma volume regulation. Trpm3-KO mice exhibited impaired tubuloglomerular feedback, reducing afferent arteriole constriction and NaCl reabsorption. CONCLUSIONS TRPM3 channels contribute to BP regulation by modulating kidney function. Blunted tubuloglomerular feedback in Trpm3-KO mice disrupts NaCl reabsorption, leading to hypovolemia and lower BP. Thus, renal TRPM3 channels may serve as promising targets for BP regulation.