Genetic deletion of TRPM8 channels restores microvascular function and mitigates chronic kidney disease progression

Chronic kidney disease (CKD) is a key public health issue. It initiates an inflammatory response and fibrotic processes, resulting in a gradual decline in kidney function. Yet, the detailed mechanism underlying the pathogenesis of chronic kidney disease remains unclear. Transient receptor potential melastatin 8 (TRPM8), a calcium (Ca²⁺) permeable, non-selective cation channel, is predominantly expressed in primary sensory neurons and plays a critical role in activating sensory neurons and regulating the inflammatory response upon stimulation. However, the interplay between TRPM8 and CKD is largely unknown. In this investigation, we used kidney samples from CKD patients and wild-type (WT) mice, TRPM8 null (TRPM8^-/-) mice with an adenine diet-fed as in vivo models, and endothelial cells (EC) with TNF-α and indoxyl sulfate (IS) treatment as an in vitro model. Our results showed that the mRNA level of TRPM8 in the kidney of CKD patients is associated with the progression of interstitial fibrosis, tubular atrophy, and proteinuria, as well as the expression of autophagy-related genes. Genetic deletion of TRPM8 in mice attenuated the adenine diet-induced increase in blood urea nitrogen and creatinine. Compared to WT mice, genetic disruption of TRPM8 alleviated the fibrotic and inflammatory response by increasing the EC integrity, autophagy flux, and antioxidant capacity. The in vitro study showed that genetic deletion of TRPM8 prevented the TNF-α and IS-induced calcium influx and EC dysfunction by increasing nitric oxide bioavailability. Collectively, our findings suggest that TRPM8 plays a crucial role in the pathogenesis of CKD and may serve as a therapeutic target for treating CKD and related renal diseases.