Modified Project Summary/Abstract Section Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD). Diabetic complications manifest themselves differently between men and women. Understanding the molecular mechanisms of these sex-related differences is critical to designing tailored therapeutic approaches. This proposal is focused on sex differences in the progression of DKD with specific emphasis on the contribution of pro-inflammatory signaling pathways in diabetic females and males. To explore the sexual dimorphisms in the development of DKD, we propose to use here non-obese type 2 diabetic nephropathy (T2DN) rats. We have demonstrated previously that T2DN rats develop renal and physiological abnormalities similar to clinical observations in humans with DKD, implying these rats are an excellent model for studying the progression of renal injury in type 2 DKD. Furthermore, our recent studies revealed sexual dimorphism in this model, indicating that while both female and male T2DN rats developed non-obese DKD phenotype, females had significant protection from the development of severe forms of glomerular and tubular damage. The main goals of this project are to determine potential molecular mechanisms causing renal, and specifically glomerular, injury and evaluate sexual dimorphism of these pathways in type 2 DKD. Aim 1 will explore the functional and structural differences between male and female T2DN rats and further identify critical sex dependent pathways in DKD. Furthermore, our pilot studies have revealed that the cyclic GMP-AMP Synthase (cGAS) / STimulator of INterferon Genes (STING) signaling pathway is upregulated in male T2DN rats and can contribute to the observed sex difference. The role of the cGAS-STING pathway in multiple regulatory mechanisms, specifically in cancer and inflammatory diseases, was recently reported. Since then, the development of drugs targeting the cGAS-STING pathway has been within the major interests of pharmaceutical companies, which provides high translational potential due to the possibility of repurposing already approved drugs. The potential role of the STING pathway in renal inflammation and fibrosis was also uncovered. Furthermore, it was proposed that the cGAS-STING pathway plays a key role in podocytopathy and modulating DKD. However, the contribution of this pathway towards the development of DKD and its role in observed differences in female and male diabetic subjects have not been established. Based on our pilot studies, we hypothesize that the cGAS-STING pathway contributes to the progression of DKD and sexual dimorphism, which will be explored in Aim 2. A combination of in vivo and ex vivo studies will be used to address the following Specific Aims: 1) To characterize the sexual dimorphisms in the progression of type 2 DKD; and 2) To define the contribution of the cGAS-STING signaling pathway in the progression of DKD and its contribution to sex difference.