SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Abstract

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.

Metadata

Item Type:	Article
Authors/Creators:	Jansen, J. https://orcid.org/0000-0003-0513-6102 Reimer, K.C. https://orcid.org/0000-0002-7118-9133 Nagai, J.S. https://orcid.org/0000-0002-7655-7206 Varghese, F.S. https://orcid.org/0000-0002-7900-5482 Overheul, G.J. https://orcid.org/0000-0002-8356-8165 de Beer, M. https://orcid.org/0000-0002-0630-4182 Roverts, R. Daviran, D. https://orcid.org/0000-0003-3229-1255 Fermin, L.A.S. https://orcid.org/0000-0003-0694-0063 Willemsen, B. Beukenboom, M. Djudjaj, S. https://orcid.org/0000-0003-2352-7537 von Stillfried, S. https://orcid.org/0000-0002-5260-8494 van Eijk, L.E. Mastik, M. Bulthuis, M. Dunnen, W.D. https://orcid.org/0000-0002-4168-1207 van Goor, H. https://orcid.org/0000-0002-6670-1577 Hillebrands, J.-L. https://orcid.org/0000-0003-3135-3274 Triana, S.H. https://orcid.org/0000-0003-0370-7821 Alexandrov, T. https://orcid.org/0000-0001-9464-6125 Timm, M.-C. van den Berge, B.T. van den Broek, M. https://orcid.org/0000-0002-1956-9921 Nlandu, Q. https://orcid.org/0000-0002-0486-4303 Heijnert, J. Bindels, E.M.J. https://orcid.org/0000-0001-9502-669X Hoogenboezem, R.M. Mooren, F. Kuppe, C. https://orcid.org/0000-0003-4597-9833 Miesen, P. https://orcid.org/0000-0002-6378-0871 Grünberg, K. https://orcid.org/0000-0003-1164-4365 Ijzermans, T. Steenbergen, E.J. Czogalla, J. Schreuder, M.F. https://orcid.org/0000-0001-9725-4856 Sommerdijk, N. Akiva, A. https://orcid.org/0000-0003-0414-889X Boor, P. https://orcid.org/0000-0001-9921-4284 Puelles, V.G. https://orcid.org/0000-0002-7735-5462 Floege, J. Huber, T.B. https://orcid.org/0000-0001-7175-5062 van Rij, R.P. Costa, I.G. https://orcid.org/0000-0003-2890-8697 Schneider, R.K. Smeets, B. https://orcid.org/0000-0002-8466-3367 Kramann, R. Achdout, H. Aimon, A. Bar-David, E. Barr, H. Ben-Shmuel, A. Bennett, J. Boby, M.L. Borden, B. Bowman, G.R. Brun, J. BVNBS, S. Calmiano, M. Carbery, A. Cattermole, E. Chernychenko, E. Choder, J.D. Clyde, A. Coffland, J.E. Cohen, G. Cole, J. Contini, A. Cox, L. Cvitkovic, M. Dias, A. Donckers, K. Dotson, D.L. Douangamath, A. Duberstein, S. Dudgeon, T. Dunnett, L. Eastman, P.K. Erez, N. Eyermann, C.J. Fairhead, M. Fate, G. Fearon, D. Federov, O. Ferla, M. Fernandes, R.S. Ferrins, L. Foster, R. https://orcid.org/0000-0002-2361-3884 Foster, H. Gabizon, R. Garcia-Sastre, A. Gawriljuk, V.O. Gehrtz, P. Gileadi, C. Giroud, C. Glass, W.G. Glen, R. Itai glinert Godoy, A.S. Gorichko, M. Gorrie-Stone, T. Griffen, E.J. Hart, S.H. Heer, J. Henry, M. Hill, M. Horrell, S. Hurley, M.F.D. Israely, T. Jajack, A. Jnoff, E. Jochmans, D. John, T. De Jonghe, S. Kantsadi, A.L. Kenny, P.W. Kiappes, J.L. Koekemoer, L. Kovar, B. Krojer, T. Lee, A.A. Lefker, B.A. Levy, H. London, N. Lukacik, P. Macdonald, H.B. Maclean, B. Malla, T.R. Matviiuk, T. McCorkindale, W. McGovern, B.L. Melamed, S. Michurin, O. Mikolajek, H. Milne, B.F. Morris, A. Morris, G.M. Morwitzer, M.J. Moustakas, D. Nakamura, A.M. Neto, J.B. Neyts, J. Nguyen, L. Noske, G.D. Oleinikovas, V. Oliva, G. Overheul, G.J. Owen, D. Psenak, V. Pai, R. Pan, J. Paran, N. Perry, B. Pingle, M. Pinjari, J. Politi, B. Powell, A. Puni, R. Rangel, V.L. Reddi, R.N. Reid, S.P. Resnick, E. Ripka, E.G. Robinson, M.C. Robinson, R.P. Rodriguez-Guerra, J. Rosales, R. Rufa, D. Schofield, C. Shafeev, M. Shaikh, A. Shi, J. Shurrush, K. Sing, S. Sittner, A. Skyner, R. Smalley, A. Smilova, M.D. Solmesky, L.J. Spencer, J. Strain-Damarell, C. Swamy, V. Tamir, H. Tennant, R. Thompson, W. Thompson, A. Thompson, W. Tomasia, S. Tumber, A. Vakonakis, I. van Rij, R.P. van Geel, L. Varghese, F.S. Vaschetto, M. Vitner, E.B. Voelz, V. Volkamer, A. von Delft, F. von Delft, A. Walsh, M. Ward, W. Weatherall, C. Weiss, S. White, K.M. Wild, C.F. Wittmann, M. Wright, N. Yahalom-Ronen, Y. Zaidmann, D. Zidane, H. Zitzmann, N.
Copyright, Publisher and Additional Information:	© 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:	SARS-CoV-2; human iPSC kidney organoids; COVID-19; kidney injury; fibrosis; protease blocker; chronic kidney disease
Dates:	Published: 3 February 2022 Published (online): 25 December 2021 Accepted: 16 December 2021
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	29 Apr 2024 13:39
Last Modified:	29 Apr 2024 14:25
Status:	Published
Publisher:	Elsevier
Identification Number:	10.1016/j.stem.2021.12.010
Related URLs:	PubMed URL Dataset Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:211975