Attenuation of SARS-CoV-2 infection by losartan in human kidney organoids

被引:14
作者
Rahmani, Waleed [1 ,2 ]
Chung, Hyunjae [2 ]
Sinha, Sarthak [3 ]
Bui-Marinos, Maxwell P. [2 ,4 ,5 ]
Arora, Rohit [3 ]
Jaffer, Arzina [3 ]
Corcoran, Jennifer A. [2 ,4 ,5 ]
Biernaskie, Jeff [3 ,6 ,7 ]
Chun, Justin [1 ,2 ]
机构
[1] Univ Calgary, Hlth Res Innovat Ctr 4A12, Cumming Sch Med, Dept Med, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada
[2] Univ Calgary, Cumming Sch Med, Calvin Phoebe & Joan Snyder Inst Chron Dis, Calgary, AB, Canada
[3] Univ Calgary, Fac Vet Med, Dept Comparat Biol & Expt Med, Heritage Med Res Bldg,Room 402,3300 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
[4] Univ Calgary, Microbiol Immunol & Infect Dis Dept, Calgary, AB, Canada
[5] Univ Calgary, Charbonneau Canc Res Inst, Calgary, AB, Canada
[6] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada
[7] Univ Calgary, Alberta Childrens Hosp Res Inst, Calgary, AB, Canada
关键词
RESPIRATORY SYNDROME CORONAVIRUS; RENIN-ANGIOTENSIN SYSTEM; CONVERTING ENZYME-INHIBITION; II RECEPTOR BLOCKERS; SPIKE PROTEIN; CELL ENTRY; FUNCTIONAL RECEPTOR; ACE2; COVID-19; TROPISM;
D O I
10.1016/j.isci.2022.103818
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
COVID-19-associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. The susceptibility of human kidneys to direct SARS-CoV-2 infection and modulation of the renin-angiotensin II signaling (RAS) pathway by viral infection remain poorly characterized. Using induced pluripotent stem cell-derived kidney organoids, SARS-CoV-1, SARSCoV-2, and MERS-CoV tropism, defined by the paired expression of a host receptor (ACE2 , NRP1 or DPP4) and protease (TMPRSS2 , TMPRSS4 , FURIN , CTSB or CTSL), was identified primarily among proximal tubule cells. Losartan, an angiotensin II receptor blocker being tested in patients with COVID-19, inhibited angiotensin II-mediated internalization of ACE2, upregulated interferon -stimulated genes (IFITM1 and BST2) known to restrict viral entry, and attenuated the infection of proximal tubule cells by SARS-CoV-2. Our work highlights the susceptibility of proximal tubule cells to SARS-CoV-2 and reveals a putative protective role for RAS inhibitors during SARS-CoV-2 infection.
引用
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页数:25
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