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Deregulated profiles of urinary microRNAs may explain podocyte injury and proximal tubule dysfunction in normoalbuminuric patients with type 2 diabetes mellitus
  1. Oana Milas1,2,
  2. Florica Gadalean1,2,
  3. Adrian Vlad2,3,
  4. Victor Dumitrascu2,4,
  5. Cristina Gluhovschi1,2,
  6. Gheorghe Gluhovschi1,2,
  7. Silvia Velciov1,2,
  8. Roxana Popescu2,5,
  9. Flaviu Bob1,2,
  10. Petru Matusz2,6,
  11. Agneta-Maria Pusztai2,6,
  12. Octavian M Cretu2,7,
  13. Alina Secara1,2,
  14. Anca Simulescu1,2,
  15. Sorin Ursoniu2,8,9,
  16. Daliborca Vlad2,4,
  17. Ligia Petrica1,2,9
  1. 1Department of Nephrology, County Emergency Hospital Timisoara, Timisoara, Romania
  2. 2‘Victor Babes’ University of Medicine and Pharmacy, Timisoara, Romania
  3. 3Department of Diabetes and Metabolic Diseases, County Emergency Hospital Timisoara, Timisoara, Romania
  4. 4Department of Pharmacology, Timisoara, Romania
  5. 5Department of Cellular and Molecular Biology, Timisoara, Romania
  6. 6Department of Anatomy and Embryology, Timisoara, Romania
  7. 7Department of Surgery I, Timisoara, Romania
  8. 8Department of Public Health Medicine, Timisoara, Romania
  9. 9Centre of Translational Research and Systems Medicine, Timisoara, Romania
  1. Correspondence to Dr Florica Gadalean, Department of Nephrology, County Emergency Hospital Timisoara, Timisoara 300125, Romania; fnnicorici{at}yahoo.com

Abstract

MicroRNAs (miRNAs) are short non-coding RNA species that are important post-transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-β-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM.

  • diabetes complications
  • rna, messenger

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Footnotes

  • Gheorghe Gluhovschi deceased.

  • DV and LP contributed equally.

  • Contributors OM and AV made substantial contributions to conception and design, analysis and interpretation of data. FG, AlS, and AnS did acquisition of data, drafting of the article, and IT technical assistance. VD did biochemical and ELISA assessments, analysis and interpretation of data. CG and FB did acquisition of data. GG revised the manuscript critically for important intellectual content. RP and DV did biochemical and ELISA assessments, and miRNAs assessments. SV did analysis and interpretation of data. PM did acquisition of data, analysis and interpretation of data, and drafting of the article. A-MP and OMC did design, analysis, and interpretation of data. SU did statistical analysis and interpretation of data. LP made substantial contributions to conception, design, analysis and interpretation of data, drafting of the article, and final approval of the version to be published. RP and DV contributed equally to the article. All authors are in agreement with the content of the manuscript.

  • Funding This research received funding from an Internal Grant of ’Victor Babes' University of Medicine and Pharmacy Timisoara, PIII-C5-PCFI-2017/2018.

  • Disclaimer The supporting source had no involvement in study design, in collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the manuscript for publication.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The County Emergency Hospital Timisoara Ethical Committee (Board of Human Studies) approved the protocol (approval number 12/20 February 2016).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First. The equal contributor statement has been updated to read: ’DV and LP contributed equally'.

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