Arteriolar hyalinosis in kidneys is an independent predictor of
cardiovascular disease, the main cause of mortality in
chronic kidney disease (CKD). The underlying molecular mechanisms of
protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and
acute kidney injury in the Kidney
Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were evaluated. Co-expression network analysis of the endothelial genes yielded three gene set modules as significantly associated with arteriolar hyalinosis. Pathway analysis of these modules showed enrichment of
transforming growth factor beta /
bone morphogenetic protein (TGFβ / BMP) and
vascular endothelial growth factor (
VEGF) signaling pathways in the endothelial cell signatures.
Ligand-receptor analysis identified multiple
integrins and cell adhesion receptors as over-expressed in arteriolar hyalinosis, suggesting a potential role of
integrin-mediated TGFβ signaling. Further analysis of arteriolar hyalinosis associated endothelial module genes identified focal segmental glomerular
sclerosis as an enriched term. On validation in gene expression profiles from the
Nephrotic Syndrome Study Network cohort, one of the three modules was significantly associated with the composite endpoint (> 40% reduction in estimated glomerular filtration rate (eGFR) or
kidney failure) independent of age, sex, race, and baseline eGFR, suggesting poor prognosis with elevated expression of genes in this module. Thus, integration of structural and single cell molecular features yielded biologically relevant gene sets, signaling pathways and
ligand-receptor interactions, underlying arteriolar hyalinosis and putative targets for therapeutic intervention.