Sexual dimorphisms and role of cGAS-STING Pathway in T2DN rats
Diabetes and its renal complications are becoming an epidemic in the U.S. population. Diabetic kidney disease (DKD) is the leading cause of chronic renal pathology and, therefore, is the subject of major research efforts. DKD is one of the primary missions of the National Institute of Diabetes and Digestive and Kidney. Importantly, as described on the DiaComp website, diabetic complications manifest themselves differently between men and women. Understanding the molecular underpinnings of these manifestations is critical to designing tailored therapeutic approaches. This proposal is focused on sex differences in the progression of DKD. To explore the sexual dimorphisms in the development of DKD, we propose to use here type 2 diabetic nephropathy (T2DN) rats. Type 2 diabetes in T2DN rats is accompanied by renal histologic abnormalities that are characteristic of DN, similar to clinical observations in human patients. T2DN model was also successfully used to evaluate several drugs and signaling pathways supporting its use as a model of DKD. This project aims to determine phenotypic characteristics of DKD progression related to the sex difference in T2DN rats and identify potential mechanisms responsible for renal injury. Our preliminary data suggests the functional divergence between the kidney injury and DKD progression in male and female T2DN rats, similar to clinical observations in human patients. Aim 1 will further explore these functional and structural differences between male and female T2DN rats using gonadectomized animals. Furthermore, our pilot studies have revealed that the cyclic GMP -AMP synthase (cGAS) / Stimulator of interferon genes (STING) signaling pathway is differently regulated between male and female T2DN rats. Role of cGAS -STING pathway in multiple regulatory mechanisms, including renal inflammation, was recently reported, and we hypothesize that this pathway contributes towards the progression of DKD and sexual dimorphism. Therefore, aim 2 will provide mechanistic insight about potential mechanisms of sex differences in type 2 DN. A combination of in vivo and ex vivo studies will be used to address the following Specific Aims: Aim 1) To characterize the sexual dimorphisms in the progression of DKD in T2DN rats; and Aim 2) To define the contribution of the cGAS-STING signaling pathway in the progression of DKD and its contribution to sex difference.

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