Hyperglycemia, inflammation and proximal tubular dysfunction contribute to the pathogenesis of diabetic nephropathy (DN), the leading cause of end-stage renal disease. Yet, the exact molecular signaling pathways underlying the development of DN are largely unknown. The endocannabinoid (eCB) system is critically involved in the onset of DN and globally-acting cannabinoid-1 (CB1) receptor antagonists were found effective in attenuating the development of DN and improving renal function. However, this treatment approach is no longer valid due to increasing centrally-mediated psychiatric side effects observed with rimonabant, the first-in-class commercially available CB1 inverse agonist.
My recent work has demonstrated that peripherally restricted CB1 antagonism may represent a novel approach to treat obesity and its related diabetic abnormalities without causing CNS-mediated side effects. Here, we propose to uncover the role of CB1 in the renal proximal tubular cells in the pathogenesis of DN, and the therapeutic potential of its blockade by peripherally restricted CB1 antagonist for the treatment of DN.
Our general hypothesis is that overactivation of the eCB system targets proximal tubular CB1 receptors to increase proteinuria, inflammation and nephropathy, leading to DN. The rationale for the proposed research is that understanding the contribution of the eCB system to the development of DN has the potential to translate into better understanding of the causes of the disease and identifying potential mechanisms that can be targeted for therapy.
Key words: Diabeteic nephropathy, CB1 receptor, Endocannabinoids, Renal dysfunction, Inflammation, Proteinuria