Deregulated Profiles of Urinary Micrornas May Explain Podocyte Injury and Proximal Tubule Dysfunction in Normoalbuminuric Patients with Type 2 Diabetes Mellitus

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 -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 (R=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R=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.

Association between Renal Podocalyxin Expression and Renal Dysfunction in Patients with Diabetic Nephropathy: A Single‐Center, Retrospective Case‐Control Study

“…Ye et al [36] and Hara et al [37] showed that positive urinary PCX could be used as a noninvasive marker of earlystage DN. The urinary and plasma levels of some miRNAs were associated with the urinary levels of PCX and were also associated with proximal tubule injury [38,39]. Metformin has been shown to restore PCX expression in diabetic rats [40], but a study suggested that dipeptidyl peptidase-4 (DDP-4) inhibitors and α-glucosidase inhibitors did not change the urinary levels of PCX [41].…”

The Biochemical Relevance of Different Types of Oxidative Stress at the Ocular Level

“…The ocular surface is very vulnerable to oxidative stress and its properties change as a result of stress. Microand macro vessels are affected by hyperglycaemia, endothelial cells become dysfunctional and play a critical role in severe changes along the vascular wall [22].…”

Long noncoding RNAs may impact podocytes and proximal tubule function through modulating miRNAs expression in Early Diabetic Kidney Disease of Type 2 Diabetes Mellitus patients

“…The serum and urinary specimens of patients and controls utilized for the assessment of UACR, cystatin C, KIM-1, NAG, synaptopodin, and podocalyxin were frozen at -80 °C and thawed before assay. Urinary biomarkers were evaluated in the same first morning urine sample 8 , 19 , 20 . The biomarkers of podocyte injury (synaptopodin, podocalyxin) and of PT dysfunction (KIM-1, NAG), were reported as per urinary creatinine ratio.…”

“…MiRNAs with negative or protective roles, either at renal level or both at renal and vascular level, have been thoroughly studied in the course of DKD 4 , 5 , 6 , 7 , 8 .…”

“…MiRNAs 21 and 124 have been proved to enhance podocyte injury and PT lesions 6 , 7 , 8 , 9 , 10 , while other miRNAs proved to be protective at the same levels, such as miRNA 192, 125a, 126, 146a 6 , 7 , 8 .…”