Loss of Kidney Microvasculature during Aging Is Dependent on Several Pathways: A Study in African Turquoise Killifish

Background: It has been proposed that age-related kidney dysfunction and chronic kidney disease are closely associated with the loss of microvasculature, microvascular rarefaction. However, microvascular rarefaction has not been studied in an aging model and the underlying mechanisms are unclear. Methods: We analyzed vascular density of aging kidneys in a novel aging model, African turquoise killifish (Nothobranchius furzeri), with natural lifespan of 4-6 months and phenotypical signs of aging. We tested the effects of aging on microvascular structure in different organs (kidney as well as heart and liver). Microvascular density was analyzed by histology, immunostaining and in-situ hybridization. We further used single nuclei RNA sequencing (snucRNAseq). Results: We were able to observe a significant reduction of the kidney microvasculature in aged kidneys. The loss of vascular density was most prominent in the kidney (63.3%), followed by heart (53.35%) and liver (49.2%). We observed a significant change in gene expression in molecular pathways of endothelial cell differentiation and metabolism. Conclusion: Our results provide a better understanding of microvascular loss and allow the identification of novel treatment targets to prevent microvascular loss in aging kidneys.