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Maladaptive proximal tubular (PT) epithelial cells have been implicated in progression of chronic kidney disease (CKD), however the complexity of epithelial cell states within the fibrotic niche remains incompletely understood. Hence, we integrated snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease. We demonstrate that in injured kidneys, a subset of HAVCR1 + VCAM1 + PT cells acquired an inflammatory phenotype, upregulating genes encoding chemokines, pro-fibrotic and senescence-associated proteins and adhesion molecules including ICAM1 . Spatial transcriptomic and multiplex-immunofluorescence determined that specifically these VCAM1 + ICAM1 + inflammatory PT cells localised to the fibrotic niche. Ligand-receptor analysis highlighted paracrine signaling from inflammatory PT cells mediating leucocyte recruitment and myofibroblast activation. Loss of HNF4α and activation of NF-κβ and AP-1 transcription factors epigenetically imprinted the inflammatory phenotype. Targeting inflammatory tubular cells by administering an AP-1 inhibitor or senolytic agent ameliorated inflammation and fibrosis in murine models of kidney injury, hence these cells may be a tractable target in CKD. The complexity of epithelial cell states in the fibrotic niche in the context of chronic kidney disease remains incompletely understood. Here the authors integrate snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease.

MicroRNAs may act as diagnostic and prognostic biomarkers of chronic kidney disease and are functionally important in disease pathogenesis. To identify novel microRNA biomarkers, we performed small RNA-sequencing on plasma from individuals with type 2 diabetes, with and without chronic kidney disease. MiR-190a-5p abundance was significantly lower in the circulation of type 2 diabetic patients with reduced function compared to those with normal kidney function. In an independent cohort of patients with chronic kidney disease of diverse aetiology, miR-190a-5p abundance predicted disease progression in individuals with no or moderate albuminuria ( < 300 mg/mmol). miR-190a-5p expression in kidney biopsy tissue correlated with the level of miR-190a-5p in the circulation and with estimated glomerular filtration rate, tubular mass and negatively with histological fibrosis. Administration of a miR-190a-5p mimic in a murine ischaemia-reperfusion injury model in male mice reduced tubular injury and fibrosis and increased expression of genes associated with tubular health. Our analyses suggest that miR-190a-5p is a biomarker of tubular cell health, low circulating levels may predict chronic kidney disease progression independent of existing risk factors and strategies to preserve miR-190a-5p may be an effective treatment for restoring tubular cell health following kidney injury. Chronic Kidney Disease affects 1 in 10 people worldwide with prevalence continuing to rise, thus there is a need to identify novel biomarkers that can add value to existing clinical and biochemical risk predictors. Here the authors identify miR190a-5p as potential indicator of kidney health and disease progression in patients with chronic kidney disease.