Mechanistic Insight of Transient Receptor Potential Melastatin 8 Role in Streptozotocin Induced Diabetic Nephropathy

Abstract

Background: The transient receptor potential melastatin 8 (TRPM8) channel is a cold-sensing non-selective cation channel involved in cellular proliferation and signaling, yet its role in diabetic nephropathy (DN) remains poorly characterized. The TRPM8 agonist, geraniol (GE) is a dietary acyclic monoterpene alcohol known for its anti-oxidant, hypoglycemic and renal chemoprotective potentials. This study aims at defining the role of TRPM8 via the use of its agonist GE in an animal model of diabetic nephropathy. Methods: A total of 80 male Wistar rats were equally divided into 4 equal groups: control, GE sham, diabetic rats received a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg) and STZ+GE diabetic rats received GE orally at a dose of (100 mg/kg/day). Indices of DNA damage, 8- Hydroxyguanosine (8-OHdG), nephrotoxicity and metabolic derangement parameters were measured eight weeks after diabetes induction. Real-time PCR was performed to detect mRNA expression levels of renal TRPM8 and podocyte marker. Renal histopathological and ultrastructural changes were recorded. Western blotting and immunohistochemistry were performed to determine TRPM8 protein expression. Results: Diabetic rats displayed downregulation of TRPM8 mRNA and protein expression levels in renal tissues. Upon administration of GE, biochemical, ultrastructural and oxidative stress findings were significantly improved in treated diabetic animals compared to control groups and coincided with upregulation of renal TRPM8 expression as well as enhancement of podocytopathy. Conclusion: The present study revealed that the ameliorative effect of GE in DN is TRPM8 mediated and highlights a mechanistic role of TRPM8 and its agonists in management of diabetic renal complications.