Palau González, VanesaNugraha, BramastaBenito, DavidPascual Santos, JulioEmmert, Maximilian Y.Hoerstrup, Simon P.Riera, MartaSoler, María José2021-09-232021-09-232021Palau V, Nugraha B, Benito D, Pascual J, Emmert MY, Hoerstrup SP, Riera M, Soler MJ. Both specific endothelial and proximal tubular Adam17 deletion protect against diabetic nephropathy. Int J Mol Sci. 2021;22(11):5520. DOI: 10.3390/ijms221155201422-0067http://hdl.handle.net/10230/48492ADAM17 is a disintegrin and metalloproteinase capable of cleaving the ectodomains of a diverse variety of molecules including TNF-α, TGF-α, L-selectin, and ACE2. We have previously demonstrated that renal ADAM17 is upregulated in diabetic mice. The role of endothelial (eAdam17) and proximal tubular (tAdam17) Adam17 deletion in renal histology, modulation of the renin angiotensin system (RAS), renal inflammation, and fibrosis was studied in a mouse model of type 1 Diabetes Mellitus. Moreover, the effect of Adam17 deletion in an in vitro 3D cell culture from human proximal tubular cells under high glucose conditions was evaluated. eAdam17 deletion attenuates renal fibrosis and inflammation, whereas tAdam17 deletion decreases podocyte loss, attenuates the RAS, and decreases macrophage infiltration, α-SMA and collagen accumulation. The 3D in vitro cell culture reinforced the findings obtained in tAdam17KO mice with decreased fibrosis in the Adam17 knockout spheroids. In conclusion, Adam17 deletion either in the endothelial or the tubular cells mitigates kidney injury in the diabetic mice by targeting different pathways. The manipulation of Adam17 should be considered as a therapeutic strategy for treating DN.application/pdfeng© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/ijms221155203D proximal tubular spheroidsADAM17Diabetic nephropathyEndothelial deletionRenal proximal tubular deletioninfo:eu-repo/semantics/openAccess