Acute kidney injury-induced circulating TNFR1/2 elevations correlate with persistent kidney injury and progression to fibrosis

Arthanarisami, A.; Komaru, Y.; Katsouridi, C.; Schumacher, J.; Verges, D. K.; Ning, L.; Abdelmageed, M. M.; Herrlich, A.; Kefaloyianni, E.

doi:10.1101/2023.04.03.534558

bioRxiv · 10.1101/2023.04.03.534558

Acute kidney injury-induced circulating TNFR1/2 elevations correlate with persistent kidney injury and progression to fibrosis

Arthanarisami, A.·Komaru, Y.·Katsouridi, C.·Schumacher, J.·Verges, D. K.·Ning, L.·Abdelmageed, M. M.·Herrlich, A.·Kefaloyianni, E.

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Abstract

BackgroundElevated levels of circulating Tumor-Necrosis-Factor-Receptors 1 and 2 (cTNFR1/2) predict CKD progression. Whether acute kidney injury drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remains unknown. MethodsWe used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, toxic) and progression to fibrosis, nephrectomy, and related single cell RNA-sequencing datasets. ResultsWe show that TNFR1/2 serum and urine levels are highly elevated in all mouse models of kidney injury tested, beginning within one-hour post-injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with severity of kidney failure. Interestingly, the extracellular vesicle (EV)-bound forms of cTNFR1/2 correlate with renal function better than their soluble forms. TNF neutralization does not affect early cTNFR1/2 elevations, suggesting that cTNFR1/2 levels do not reflect injury-induced TNF activity. Kidney tissue expression of TNFR1/2 after AKI is only mildly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting release of these receptors by extrarenal sources. cTNFR1/2 remain elevated for weeks after severe kidney injury and at these later timepoints cTNFR1/2 correlate to remaining kidney injury. During AKI-to-CKD transition, kidney expression of TNFR1/2 and cTNFR2 levels, correlate with development of fibrosis. ConclusionsOur data demonstrate that AKI drives acute increases in cTNFR1/2 serum levels which negatively correlate with kidney function, in particular their EV-bound forms. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition correlate with persistent tissue injury and progression to kidney fibrosis. Significance StatementCirculating TNF-Receptor-1 and -2 (cTNFR1/2) elevations predict chronic kidney disease progression. It remains unknown whether kidney injury can drive cTNFR1/2 elevations, whether cTNFR1/2 levels predict disease outcomes after AKI, and which are their circulating molecular forms. This study shows that kidney injury strongly increases cTNFR1/2 levels and that their extracellular vesicle-bound forms better correlate with kidney function loss, compared to their soluble forms. Sustained cTNFR1/2 elevations correlate to remaining kidney injury, and cTNFR1/2 levels post injury predict progression to kidney fibrosis. This work, thus, points to novel mechanisms for the observed cTNFR1/2 elevations in kidney disease and identifies unique predictive and diagnostic value in cTNFR1/2 elevations in AKI or AKI-to-CKD transition.

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Arthanarisami, A., Komaru, Y., Katsouridi, C., Schumacher, J., Verges, D. K., Ning, L., Abdelmageed, M. M., Herrlich, A., Kefaloyianni, E.. 2023-04-04. Acute kidney injury-induced circulating TNFR1/2 elevations correlate with persistent kidney injury and progression to fibrosis. https://doi.org/10.1101/2023.04.03.534558

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