Abstract
Dear Editor,
Diabetic kidney disease (DKD) remains one of the most serious microvascular complications of type 2 diabetes mellitus (T2DM), contributing substantially to end-stage renal disease (ESRD). Current diagnostic markers such as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) lack sensitivity for early detection, underscoring the need for novel serum biomarkers.
MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers in diabetic complications due to their stability in circulation and involvement in pathways linked to renal fibrosis, inflammation, and endothelial dysfunction. However, data on miRNA expression in Middle Eastern populations remain limited.
We conducted a cross-sectional study of 103 Emirati participants, including T2DM patients with DKD (n = 36), without DKD (n = 51), and healthy controls (n = 16). DKD was diagnosed and stratified into micro- and macroalbuminuria using ADA criteria. Serum expression of four candidate miRNAs (miR-21-5p, miR-22e, miR-29a-3p, miR-126-3p) and their target genes (PTEN, TGF-β) was measured by qPCR, with 18S rRNA as the reference.
Our results revealed distinct expression signatures (Figure 1). PTEN was significantly downregulated in DKD compared to non-DKD (p = 0.0018) and healthy controls (p < 0.0001). Among circulating miRNAs, miR-21-5p and miR-22e were upregulated in DKD, while miR-126-3p and miR-29a-3p were progressively downregulated, particularly in macroalbuminuria. These findings align with established roles of these miRNAs in fibrosis, vascular dysfunction, and podocyte injury. In contrast, TGF-β expression showed no significant group differences, possibly reflecting treatment-related modulation. Expression of four candidate circulating miRNAs in T2DM subgroups compared to healthy controls. Bar plots represent mean log2 fold change (FC) relative to controls. (a) miR-21-5p: upregulated in micro- and macroalbuminuria; (b) miR-22e: elevated in microalbuminuria; (c) miR-126-3p: downregulated in DKD; (d) miR-29a-3p: progressively reduced across DKD severity. Error bars indicate standard deviation.
Interestingly, miR-22e levels in macroalbuminuria appeared closer to those of healthy controls. This may reflect compensatory regulation or treatment-related modulation at advanced disease stages, where long-term pharmacotherapy (e.g., RAAS blockade, statins, or antidiabetic agents) could alter miRNA expression profiles. Another possibility is that chronic renal injury leads to loss of specific cell types contributing to circulating miR-22e, thereby masking its elevation seen in earlier disease stages.
These data suggest that miR-21-5p, miR-22e, and miR-126-3p may serve as potential serum biomarkers for early DKD detection, with PTEN downregulation supporting their mechanistic relevance. Notably, this is among the first studies to report miRNA expression patterns associated with DKD in an Emirati population, addressing a critical gap in molecular epidemiology from the Middle East.
The study has limitations, including modest sample size, cross-sectional design, and lack of detailed medication adjustment, all of which may influence gene expression. Larger longitudinal studies with stratified analyses are required to validate these findings and assess their predictive value.
In conclusion, our findings highlight the potential of circulating miRNAs, particularly miR-21-5p, miR-22e, and miR-126-3p, as minimally invasive biomarkers for DKD among Emirati patients with T2DM. PTEN downregulation further underscores the involvement of miRNA-regulated pathways in DKD pathogenesis. Future work integrating miRNA profiling with clinical risk stratification may improve early detection and guide targeted interventions.
Sincerely,
Zuira Tariq, Rifat Akram Hamoudi, Bashair M. Mussa, Poorna Bhamidimarri, Zainab AL-Abadla, Rawoof Khan, Salah Abusnana
