During the last few decades, there has been an epidemic increase worldwide in the prevalence of obesity and its metabolic and cardiovascular disorders. In addition, obesity has been increasingly recognized as an independent key factor in the development of renal complications, yet the underlying signaling pathways are not fully understood. Cannabinoid type-1 (CB1) receptor plays an important role in the onset of nephropathy associated with diabetes, and globally-acting CB1 receptor antagonists were found effective in improving renal function.
In this project, we propose to uncover the role of CB1, specifically in the renal proximal tubule, in obesity-induced renal dysfunction. Our general hypothesis is that increased activity of the renal endocannabinoid (eCB) system in obesity targets CB1 receptors in the renal proximal tubular cells (RPTCs) to promote RPTC dysfunction, and thus may contribute to the development of obesity-induced renal nephropathy.
To test this hypothesis, we will determine the metabolic and renal phenotypes associated with high-fat diet-induced obesity in a novel mouse strain that lacks CB1 receptors in the RPTCs. The rationale for the proposed research is that understanding the contribution of CB1/eCB system to the development of obesity-related kidney dysfunction has the potential to be translated into better understanding of the causes of the disease, and identifying potential mechanisms that can be targeted for therapy. This could support the development and clinical testing of pharmacological strategies, such as peripheral CB1 receptor antagonists for the treatment of not only obesity per-se but also to its related renal complications.
Key words: Endocannabinoids, CB1 receptor, Obesity, Tubular inflammation & injury, Renal function, Renal fibrosis, Metabolism