A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells

被引：50

作者：

Garreta, Elena ^{[1
]}

Prado, Patricia ^{[1
]}

Stanifer, Megan L. ^{[2
,3
,4
]}

Monteil, Vanessa ^{[5
,6
]}

Marco, Andres ^{[1
]}

Ullate-Agote, Asier ^{[7
,8
,9
]}

Moya-Rull, Daniel ^{[1
]}

Vilas-Zornoza, Amaia ^{[7
,8
,9
]}

Tarantino, Carolina ^{[1
]}

Pablo Romero, Juan ^{[7
]}

Jonsson, Gustav ^{[10
]}

Oria, Roger ^{[11
]}

Leopoldi, Alexandra ^{[10
]}

Hagelkruys, Astrid ^{[10
]}

Gallo, Maria ^{[1
]}

Gonzalez, Federico ^{[1
]}

Domingo-Pedrol, Pere ^{[12
]}

Gavalda, Aleix ^{[13
,14
]}

Hurtado del Pozo, Carmen ^{[1
]}

Hasan Ali, Omar ^{[15
,16
,17
]}

Ventura-Aguiar, Pedro ^{[18
,19
]}

Maria Campistol, Josep ^{[18
,19
]}

Prosper, Felipe ^{[7
,8
,9
]}

Mirazimi, Ali ^{[5
,6
,20
]}

Boulant, Steeve ^{[3
,4
,21
]}

Penninger, Josef M. ^{[10
,15
]}

Montserrat, Nuria ^{[1
,22
,23
]}

机构：

[1] Barcelona Inst Sci & Technol BIST, Inst Bioengn Catalonia IBEC, Pluripotency Organ Regenerat, Barcelona, Spain

[2] Heidelberg Univ Hosp, Dept Infect Dis, Mol Virol, Heidelberg, Germany

[3] German Canc Res Ctr, Res Grp Cellular Polar & Viral Infect, Heidelberg, Germany

[4] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32611 USA

[5] Karolinska Inst, S-17182 Stockholm, Sweden

[6] Karolinska Univ Hosp, Unit Clin Microbiol, S-17182 Stockholm, Sweden

[7] Univ Navarra, Inst Invest Sanitaria Navarra IDISNA, Ctr Invest Med Aplicada, Area Hematooncol, Pamplona 31008, Spain

[8] Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain

[9] Univ Navarra, Clin Univ Navarra, Dept Hematol, Pamplona 31008, Spain

[10] Austrian Acad Sci, Inst Mol Biotechnol, IMBA, Dr Bohr Gasse 3, A-1030 Vienna, Austria

[11] UCSF, Ctr Bioengn & Tissue Regenerat, San Francisco, CA USA

[12] Hosp Univ Santa Creu & St Pau, Internal Med Dept, Barcelona, Spain

[13] Univ Barcelona, Inst Biomed IBUB, Dept Bioquim & Biomed Mol, Barcelona, Spain

[14] CIBER Fisiopatol Obesidad & Nutr, Barcelona, Spain

[15] Univ British Columbia, Life Sci Inst, Dept Med Genet, Vancouver, BC, Canada

[16] Univ Zurich, Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland

[17] Cantonal Hosp St Gallen, Inst Immunobiol, St Gallen, Switzerland

[18] Hosp Clin Barcelona, Nephrol & Kidney Transplant Dept, Barcelona, Spain

[19] Fundacio Clin Recerca Biomed FCRB, Lab Expt Nefrol & Trasplantament LENIT, Barcelona, Spain

[20] Natl Vet Inst, Uppsala, Sweden

[21] Heidelberg Univ Hosp, Dept Infect Dis, Virol, Heidelberg, Germany

[22] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain

[23] Ctr Invest Biomed Red Bioingn Biomat & Nanomed, Madrid, Spain

来源：

CELL METABOLISM | 2022年 / 34卷 / 06期

基金：

加拿大健康研究院; 欧盟地平线“2020”; 瑞士国家科学基金会; 芬兰科学院; 瑞典研究理事会; 欧洲研究理事会;

关键词：

ANGIOTENSIN-CONVERTING ENZYME-2; CULTURED-CELLS; DISTAL TUBULE; CORONAVIRUS; COMPLICATIONS; REVEALS; DISEASE; PROTEIN; MOUSE; SPIKE;

D O I：

10.1016/j.cmet.2022.04.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.

引用

页码：857 / +

页数：27

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