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Identification of the regulatory mechanism of ACE2 in COVID-19-induced kidney damage with systems genetics approach.
Yang, Xueling; Lin, Chunhua; Liu, Jian; Zhang, Ya; Deng, Tingzhi; Wei, Mengna; Pan, Shuijing; Lu, Lu; Li, Xuri; Tian, Geng; Mi, Jia; Xu, Fuyi; Yang, Chunhua.
  • Yang X; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China.
  • Lin C; Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264008, China.
  • Liu J; Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, 250014, China.
  • Zhang Y; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China.
  • Deng T; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China.
  • Wei M; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China.
  • Pan S; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China.
  • Lu L; Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
  • Li X; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, 510060, China.
  • Tian G; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China.
  • Mi J; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China. jia.mi@bzmc.edu.cn.
  • Xu F; Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Shandong, Yantai, 264003, China. xufuyiphd@gmail.com.
  • Yang C; Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. xufuyiphd@gmail.com.
J Mol Med (Berl) ; 101(4): 449-460, 2023 04.
Article in English | MEDLINE | ID: covidwho-2287607
ABSTRACT
Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes (Dnase1, Vasn, Usp7, Abat, Mgrn1, and Rbfox1) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc, which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44, Egfr, Met, Smad3, and Stat3 were identified as hub genes through protein-protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2, pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19-induced renal damage outcomes. KEY MESSAGES • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Experimental Studies / Prognostic study Limits: Animals Language: English Journal: J Mol Med (Berl) Journal subject: Molecular Biology / Genetics, Medical Year: 2023 Document Type: Article Affiliation country: S00109-023-02304-9

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Experimental Studies / Prognostic study Limits: Animals Language: English Journal: J Mol Med (Berl) Journal subject: Molecular Biology / Genetics, Medical Year: 2023 Document Type: Article Affiliation country: S00109-023-02304-9