Targeted Therapeutic for Diabetic Nephropathy
The prevalence of diabetes worldwide has reached epidemic magnitudes and is expected to affect more than 550 million people by the year 2035. Diabetic nephropathy (DN) is a serious complication with lifelong repercussions and a high mortality rate. Renal vascular dysfunction that occurs in both diabetes mellitus type 1 (T1DM) and diabetes mellitus type 2 (T2DM) is a major contributor to DN. There is a lack of effective and safe treatments for DN. We have identified and developed epoxyeicosatrienoic acid (EET) analogs that have the potential to oppose renal vascular dysfunction and stop the progressive loss of kidney function in diabetes. EET analogs have actions that are ideally suited to treat kidney diseases including vasodilation, inhibition of platelet adhesion, blood pressure lowering action that takes days to weeks, and long-term anti-inflammatory, anti-apoptotic, and anti-fibrotic actions over the course of weeks to months. This project aligns with the 2020 funding opportunities for DiaComp under the Targeted Delivery of Therapeutics area of interest. To meet the critical need for a DN therapeutic, this project will develop and evaluate highly efficient delivery of EET analogs to the kidney. Our central hypothesis is that that kidney targeted EET analogs will allow a reduction in the drug level needed to achieve efficacy, decrease side-effects, and enhance overall therapeutic potential for DN. Initial studies have determined that a novel kidney targeted EET analog combats cisplatin-induced nephrotoxicity at a reduced drug level. The specific aim will test the hypothesis that kidney targeted EET analogs prevent the progression of TD1 and TD2 DN. We will compare two kidney targeted EET-C22 analogs to prevent the progression of T1D and T2D DN. Experimental studies will be conducted in T1D Akita (Ins2+/C96Y) FVB/NJ mice and T2D BTBR ob/ob mice. DN progression in T1D and T2D mice treated with kidney targeted EET analogs will be compared to the standard of care, angiotensin converting enzyme (ACE) inhibition. The contribution of the proposed research is expected to provide “proof of concept” for kidney targeted EET analogs to treat DN.

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