title: MiR-204/miR-211 downregulation contributes to candidemia-induced kidney injuries via derepression of Hmx1 expression.
abstract: OBJECTIVE
  This study was aimed to exploit the role of heme oxygenase Hmx1 and the potential miRNA mechanisms in the kidney injuries induced by urinary tract infection by Candida species/Candidemia.
  
  
  METHODS
  We employed a mouse model of systemic Candidiasis by injection of the Candida albicans strain SC5314 into C57BL/6 mice. Kidney injuries were assessed by measuring serum cystatin C (CysC), serum β2-microglobulin (β2-MG) and blood urea nitrogen (BUN). Validation of miRNA target gene was conducted by luciferase reporter gene assay, Western blot analysis and real-time RT-PCR.
  
  
  RESULTS
  We showed here that Candidemia caused significant downregulation of microRNAs miR-204 and miR-211. In sharp contrast, Hmx1 expression was remarkably upregulated, particularly at the protein level. Computational analysis predicted Hmx1 as a target gene for both miR-204 and miR-211 that share the same seed site sequence. We then experimentally validated the targeting relationship between miR-204/miR-211 and Hmx1, which explains the reciprocal changes of expression of miR-204/miR-211 and Hmx1 in Candidemia. Administration of miR-204/miR-211 mimics substantially downregulated Hmx1 and mitigated the severity of the kidney injuries induced by Candidemia, as reflected by improved renal glomerular filtration rate (GFR) determined by serum cystatin C (CysC), serum β2-microglobulin (β2-MG) and blood urea nitrogen (BUN). Knockdown of miR-204/miR-211 worsened while forced expression of miR-204/miR-211 ameliorated kidney injuries in mice with systemic Candidiasis.
  
  
  CONCLUSIONS
  Our findings indicate that miR-204/miR-211 downregulation accounts at least partially for the Hmx1 upregulation and the miR-204/miR-211-Hmx1 signaling axis may contribute to immune-suppression in the host thereby the Candidemia-induced kidney dysfunction.
authors.affiliation: Department of Critical Care Medicine, Dongguan People's Hospital, Dongguan, Guangdong 523059, China.
authors.forename: Xiao-Yue
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, PLA421 Hospital, Guangzhou, Guangdong 510318, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: Jiang
authors.affiliation: Department of Critical Care Medicine, Dongguan People's Hospital, Dongguan, Guangdong 523059, China. Electronic address: cailh28@126.com.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Cai
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D058387:Candidemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014552:Urinary Tract Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D018398:Homeodomain Proteins; C574692:MIRN204 microRNA, mouse; D035683:MicroRNAs; C577982:Mirn211 microRNA, mouse; C529125:NKX5-3 protein, mouse; D014157:Transcription Factors
keywords: Candida albicans; Candidemia; Gene expression regulation; Hmx1; Kidney injuries; MiR-204; MiR-211; MicroRNA; Renal function; Renal glomerular filtration rate (GFR); Serum cystatin C (CysC); Serum β(2)-microglobulin (β(2)-MG)