Potential Role of cGAS‐STING Pathway in the Induction of Diabetic Kidney Disease

Abstract

The role of the cyclic GMP–AMP synthase (cGAS) / Stimulator of interferon genes (STING) / interferon‐β (INFβ) axis in innate immunity has been explored during the last decade. Recently, it has been revealed that the activity of this pathway could be a double‐edged sword; besides protection against invading organisms, its overactivity has been associated with pathological conditions e.g., Aicardi‐Goutieres syndrome (AGS) syndrome. It was also recently reported that activation of the STING‐cGAS pathway had been associated with renal inflammation and fibrosis. However, the impact of the cGAS‐STING pathway on diabetic kidney disease (DKD) has not been studied before. Therefore, the goal of this study was to assess the contribution of the cGAS‐STING‐INFβ pathway towards the development of DKD. We used two established DKD models that develop advanced diabetic kidney lesions ‐ eNOSdb/db mice and type 2 diabetic nephropathy (T2DN) rat. Western blot analysis was used to estimate the expression and/or activity level of different molecules involved in the cGAS‐STING pathway in the kidney tissue from 28 wks old eNOSdb/db mice and corresponding controls. RT‐qPCR was also used to test the transcriptional level of interferon genes, which are the downstream target of this pathway. Comparison between male and female in T2DN rats were used to define changes in the cGAS‐STING signaling pathway during the progression of DKD. As was previously reported, female rats exhibit significant attenuation in progression of diabetes and renal damage in this model. Western blot analysis showed increased expression and/or activity of specific proteins involved in the cGAS‐STING pathway. RT‐qPCR confirmed the Western blot results and showed a significant elevation of the checked INFβ genes. Overall, the activity of cGAS‐STING signaling was higher in males, which is consistent with the protective phenotype of T2DN female rats. In addition, immunohistochemistry (IHC) staining for STING molecule in described rodent models and human renal samples was performed. The results indicate the significant elevation of STING in the renal tissue of both rodents and humans with type 2 diabetes. Therefore, our data revealed that cGAS‐STING pathway is markedly activated in diabetes, and we speculate that inhibiting this pathway would ameliorate the deleterious outcome of the pathologic processes in DKD.