Vascular dysfunction in renal injury and cognitive dysfunction: the central role of endothelin-1.

Chronic kidney disease (CKD) is strongly associated with cognitive impairment and dementia, yet the vascular pathways linking renal injury to cognitive dysfunction remain incompletely defined. The kidney and brain rely on high-flow microvascular circuits and specialized endothelial barriers, rendering both organs vulnerable to endothelial dysfunction. Endothelin-1 (ET-1), a potent vasoactive peptide, is primarily produced by vascular endothelial cells but can also be produced by other cell types including fibroblasts and smooth muscle cells. ET-1 is becoming increasingly recognized as a convergent driver of endothelial and microvascular dysfunction across cardiovascular end-organs. In the kidney, dysregulation of the endothelin (ET) system promotes vasoconstriction, endothelial dysfunction, oxidative stress, and inflammation, accelerating the progression of CKD. In the brain, dysregulation of the ET system contributes to cerebral hypoperfusion, impaired neurovascular coupling, blood-brain-barrier disruption, and neuroinflammation. In this review, we synthesize evidence supporting ET system signaling as a mechanistic and translational bridge between renal and cerebral microvascular dysfunction and discuss how shared cardiometabolic and autoimmune risk factors may amplify ET signaling, thereby worsening kidney-brain outcomes. Lastly, we highlight the therapeutic opportunities and limitations of ET receptor antagonism, emphasizing the need for receptor- and cell-type-specific interventions to mitigate multi-organ vascular injury and preserve cognitive function in patients with CKD.