Stroke is one of the leading causes of mortality and disability worldwide, with ischemic stroke accounting for over 87% of all stroke cases. Chronic kidney disease (CKD) is one of the major risk factors for stroke, as CKD patients have shown evidence of impaired cerebral autoregulation leading to exacerbated stroke pathology. The worsening of stroke outcomes in CKD patients is limitedly understood. Inflammation plays a pivotal role in driving the CKD-stroke pathology. The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon gene) pathway acts as a key mediator of inflammation in both pathologies. As mitochondrial dysfunction plays a common connecting link between stroke and CKD, activation of the innate-immune response mediated by cGAS-STING pathway becomes inevitable. Therefore, it becomes imperative to understand the role of mitochondria in the exacerbation of stroke outcomes following CKD. In addition, the critical role of altered immune response leading to exacerbated mitochondrial dysfunction and aging in CKD-stroke complex is also crucial to investigate. To study this, CKD was induced in male Sprague Dawley rats followed by middle cerebral artery occlusion (MCAo) to develop a CKD-Stroke complex animal model. Behavioral studies were conducted, and tissues were harvested for biochemical, histological, molecular, mitochondrial and genetic studies. Our findings from transcriptomic and proteomic analyses confirm upregulation of STING, interferons and related genes, alongside downregulation of mitochondrial health markers, in the CKD-stroke complex. This molecular profile reflects accelerated mitochondrial aging due to altered innate immunity mediated by cGAS-STING pathway.
Datta et al. (2026) studied this question.