RAGE/Diaph1, Diabetes, and Kidney Disease: Mechanisms and Novel Therapeutic Strategies

ABSTRACT

In Year Three of the funded grant, we have substantial progress in the following critical areas 1). As noted in the project narrative, we generated four different lines of mice to directly test the hypothesis that RAGE and DIAPH1 contribute to the pathogenesis of diabetes-associated nephropathy in the podocytes and/or in myeloid cells/macrophages. All of the mouse lines are now generated and largely completed (mice sacrificed) and samples being evaluation by Dr DAgati. There are no new pending mice to generate all are generated and on time course. 2). We have determined that the small molecule RAGE/DIAPH1 antagonist is best administered orally and that the RAGE antagonist survives the medicated chow pelleting, heating and irradiation. Our first data on treated vs. untreated male and female diabetic mice illustrates reduction in mesangial sclerosis, reduced thickening of the glomerular basement membrane and reduction in podocyte effacement in diabetic mice receiving RAGE229 medicated chow (vs vehicle). Additional mice are on study and time course at this time to complete the indicated enrollment.3). For transcriptomics and metabolomics/lipidomics assay, Dr. Ramasamy will be testing the macrophages from the mice through the time course and he has verified all of his experimental systems for the performance of the outlined studies. Dr. Ramasamy identifies substantial progress in the development and validation of metabolomics and lipidomics assays here at NYU and in transcriptomic data (all on macrophages) in order to understand detailed mechanisms of the role of these molecules in the diabetic kidney. Taken together, despite the >3 month shutdown due to COVID19 our work in Year 3 has been productive and we await tissue and other analyses, as above, to render final conclusions.