TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha heterozygous mice.

American Journal of Physiology. Renal Physiology
Fiona M KellyJennifer L Gooch

Abstract

Calcineurin is an important intracellular signaling molecule which can be inhibited by cyclosporin resulting in immune suppression and nephrotoxicity. Previously, we reported that homozygous loss of the alpha isoform of calcineurin impairs kidney development and function and mimics many features of cyclosporin nephrotoxicity. However, early lethality of null mice prevented further study of renal changes. Alternatively, we examined aged heterozygous (CnAalpha(+/-)) mice. In addition to renal dysfunction and inflammation, we find that CnAalpha(+/-) mice spontaneously develop tertiary lymphoid aggregates in the kidney, small intestine, liver, and lung. Lymphoid aggregates contain both T cells and B cells and exhibited organization suggestive of tertiary lymphoid organs (TLOs). Kidney function and TLO formation were highly correlated suggesting that this process may contribute to nephrotoxicity. Consistent with previous findings, transforming growth factor (TGF)-beta is significantly increased in CnAalpha(+/-) mice. Neutralization of TGF-beta attenuated TLO formation and improved kidney function. In conclusion, we report that haploinsufficiency of CnAalpha causes uregulation of TGF-beta which contributes to chronic inflammation and...Continue Reading

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Citations

Jul 19, 2012·Expert Reviews in Molecular Medicine·Clintoria R Williams, Jennifer L Gooch
Sep 1, 2016·Frontiers in Immunology·Eóin N McNamee, Jesús Rivera-Nieves
Nov 23, 2013·Clinical Journal of the American Society of Nephrology : CJASN·Guangchang PeiGang Xu
Apr 10, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Siva Kumar SolletiThomas J Mariani
Jun 1, 2012·Clinical Kidney Journal·Agnieszka A PozdzikJoëlle L Nortier
Jun 16, 2021·Scientific Reports·Long T NguyenCarol A Pollock

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