Endocrine Abstracts

Context: Diabetic kidney disease (DKD) is a common microvascular complication that affects approximately 40% of patients with diabetes mellitus (DM). This complication is the leading cause of end-stage renal disease (ESRD) in patients starting renal replacement therapy and is associated with increased cardiovascular mortality. Although a tight glycemic control is able to reduce the development and delay the progression of DKD, current therapies are still not totally effective in preventing progression to ESRD. Therefore, additional mediators and mechanisms leading to DKD need to be identified for more effective diagnosis and treatment of this complication. In this context, emerging evidence suggests a role for epigenetic factors, such as microRNAs (miRNAs), in the DKD development. MiRNAs are small non-coding RNAs that regulate gene expression. Moreover, circulating miRNAs are ideal noninvasive biomarkers because they are stable in body fluids and can be detected using established techniques for quantification, such as quantitative PCR. However, the identification of the specific miRNAs expression profile involved in DKD remains incomplete.

Objective: To investigate a miRNA expression profile in plasma of type 1 DM (T1DM) patients with DKD (cases) compared to T1DM patients without DKD (controls), and to perform bioinformatic analysis to investigate the potential roles of the miRNAs.

Design: Expression of 48 miRNAs was investigated in plasma of 58 T1DM patients (23 controls, 18 with moderate DKD, and 17 with severe DKD) using Stem-loop RT-PreAmp Real-time PCR and TaqMan Low Density Array cards (Thermo Scientific Inc). Then, five differently expressed miRNAs were chosen for validation in an independent sample of 10 T1DM controls and 19 DKD cases, using RT-qPCR. Bioinformatic analyses were performed to explore the putative target genes and biological pathways regulated by these miRNAs.

Results: Nine miRNAs were differently expressed in plasma of patients with different stages of DKD (hsa-miR-141-3p, hsa-miR-16-5p, hsa-miR-192-5p, hsa-miR-204-5p, hsa-miR-21-3p, hsa-miR-215-5p, hsa-miR-29a-3p, hsa-miR-378a-5p, and hsa-miR-503-5p) compared to T1DM controls. After validation in an independent sample, hsa-miR-21-3p and hsa-miR-378-3p were upregulated; while hsa-miR-16-5p and hsa-miR-29a-3p were downregulated in DKD cases. Additionally, these miRNAs and their targets participate in pathways of known relevance for DKD pathogenesis, such as TGF-β, PI3K/Akt, longevity, AGE-RAGE signaling pathway in diabetic complications, and relaxin signaling pathways.

Conclusions: Our study demonstrates that four miRNAs were differently expressed in DKD patients, constituting potential biomarkers of this chronic diabetic complication.