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Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Spatial analysis reveals cellular microenvironments and mechanisms of inflammation and injury in acute interstitial
Megan L Baker1, Vijayakumar R Kakade2, Tifanny Budiman2
1Department of Internal Medicine/Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA. megan.baker@yale.edu.
Abstract:
Acute interstitial nephritis (AIN) is present in 15-20% of all acute kidney injury cases but lacks proven effective therapies beyond corticosteroids. Using high-resolution imaging mass cytometry and single-cell spatial transcriptomics to analyze human kidney biopsies with AIN, acute tubular injury (ATI), and reference tissue, we show that interferon-γ-induced CXCL9-CXCR3 signaling is markedly increased in AIN, with significantly more predicted interactions relative to ATI, dominated by homotypic T cell-T cell amplification networks concentrated in lymphoid aggregates. Tubular cells, predominantly VCAM1+ injured proximal tubules, markedly upregulate complement components, with local enrichment of C3AR1+ immune cells, linking tubular injury to immune activation in AIN. Nicotinamide phosphoribosyltransferase (NAMPT) is the strongest spatial correlate of VCAM1+ tubular microenvironments, with expression by both injured tubules and surrounding immune cells coordinating metabolic-inflammatory niches. These findings reveal distinct molecular circuits underlying AIN pathogenesis and nominate potential therapeutic targets for improving clinical management and preventing progression to chronic kidney disease.
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