Role of cGAS/STING pathway in aging and sexual dimorphism in diabetic kidney disease
Sherif Khedr, Lashodya V. Dissanayake, Ammar J. Alsheikh, Adrian Zietara, Denisha R. Spires, Romica Kerketta, Angela J. Mathison, Raul Urrutia, Oleg Palygin, Alexander Staruschenko
Sherif Khedr, Lashodya V. Dissanayake, Ammar J. Alsheikh, Adrian Zietara, Denisha R. Spires, Romica Kerketta, Angela J. Mathison, Raul Urrutia, Oleg Palygin, Alexander Staruschenko
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Research Article Nephrology

Role of cGAS/STING pathway in aging and sexual dimorphism in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is the leading cause of chronic renal pathology. Understanding the molecular underpinnings of DKD is critical to designing tailored therapeutic approaches. Here, we focused on sex differences and the contribution of aging toward the progression of DKD. To explore these questions, we utilized young (12 weeks old) and aged (approximately 50 weeks old) type 2 diabetic nephropathy (T2DN) rats. We revealed that the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway was upregulated in T2DN rats compared with nondiabetic Wistar rats and in type 2 diabetic human kidneys. The activation of the cGAS/STING signaling pathway exhibited distinct protein expression profiles between male and female T2DN rats, with these differences becoming more pronounced with aging. RNA-Seq analysis of the kidney cortex in both male and female T2DN rats, at both younger and older ages, revealed several key molecules, highlighting crucial genes within the cGAS/STING pathway. Thus, our study delved deep into understanding the intricate sexual differences in the development and progression of DKD and we propose the cGAS/STING pathway as an essential contributor to disease development.

Authors

Sherif Khedr, Lashodya V. Dissanayake, Ammar J. Alsheikh, Adrian Zietara, Denisha R. Spires, Romica Kerketta, Angela J. Mathison, Raul Urrutia, Oleg Palygin, Alexander Staruschenko

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Figure 6

RNA-Seq analysis of cGAS/STING-specific genes.

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RNA-Seq analysis of cGAS/STING-specific genes. (A) RPKM expression level...
(A) RPKM expression level of genes normalized to the z scale. (B) PCA plot with centroids (open circles) and different animal groups (filled circles) using RPKM expression values of genes. (C) Gene networks and upstream regulatory analysis of cGAS/STING-specific genes for different animal groups. Gene networks: significant gene fold changes (|fold change| ≥ 2 and FDR < 0.05) with respect to controls are represented in red (upregulation) and blue (downregulation) nodes, while the nonsignificant genes have white nodes. Upstream regulatory analysis: color scheme of nodes is the same as in gene networks. Yellow and purple nodes represent predicted activated or inhibited transcription factors, respectively. Orange lines indicate predicted activation, blue lines indicate predicted inhibition, yellow lines indicate that the predicted relationship is inconsistent with gene expression, while gray lines indicate no predicted effect. (D) Volcano plots of statistically significant differentially expressed genes identified from the RNA-Seq data among different groups. n = 4 rats in each group.