Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, leads to the development of fluid-filled cysts throughout the kidney. Current treatments predominantly target pathways in the kidney epithelium, but these therapies do not always prevent kidney failure. There is increasing evidence to suggest that targeting the blood vessel networks within the kidney could provide an alternative therapeutic strategy for treating ADPKD. The highly specialised kidney vasculature shows aberrant patterning in late-stage ADPKD patients, but it has so far been unclear whether aberrant vasculature has earlier origins during disease onset. Understanding the contribution of the endothelial cells that make up the kidney blood vessels to ADPKD could improve therapeutic options and provide new insight into disease progression.
In this study, Jafree, Long and colleagues investigated the molecular profiles of endothelial cells in kidney blood vessels using published single-cell and single-nucleus transcriptomic data, generating a reference atlas of endothelial cell subpopulations. They discovered one subgroup of endothelial cells unique to patients with advanced ADPKD and validated it in tissue samples using immunolabelling targeting key markers identified by transcriptional analysis. This disease-specific subpopulation was also present in the kidneys of a mouse model of ADPKD, even at the age of 3 months – an early stage that precedes decline in kidney function. At this 3-month stage, the authors also observed increased vascular disorganisation in the kidneys of the ADPKD model mice using advanced 3D imaging techniques. This aberrant vasculature was also associated with decreased renal blood flow specifically in the kidney cortex, another observation made at a stage prior to the onset of kidney failure, highlighting a role for the kidney vasculature in the development of the disease.
These results show that aberrant endothelial phenotypes and disrupted vascular structure become apparent before major functional decline in polycystic kidney disease, providing opportunities for therapeutic intervention and early detection. Understanding the role of the kidney vasculature during the early stages of disease could enable the development of alternative or complementary treatment strategies to prevent kidney failure in ADPKD patients.
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