Circulating TGF-β1-Regulated miRNAs and the Risk of Rapid Progression to ESRD in Type 1 Diabetes

Abstract

We investigated whether circulating TGF-β1-regulated miRNAs detectable in plasma are associated with the risk of rapid progression to end-stage renal disease (ESRD) in a cohort of proteinuric patients with type 1 diabetes (T1D) and normal eGFR. Plasma specimens obtained at entry to the study were examined in two prospective subgroups that were followed for 7-20 years (rapid progressors and nonprogressors), as well as a reference panel of normoalbuminuric T1D patients. Of the five miRNAs examined in this study, let-7c-5p and miR-29a-3p were significantly associated with protection against rapid progression and let-7b-5p and miR-21-5p were significantly associated with the increased risk of ESRD. In logistic analysis, controlling for HbA1c and other covariates, let-7c-5p and miR-29a-3p were associated with more than a 50% reduction in the risk of rapid progression (P ≤ 0.001), while let-7b-5p and miR-21-5p were associated with a >2.5-fold increase in the risk of ESRD (P ≤ 0.005). This study is the first prospective study to demonstrate that circulating TGF-β1-regulated miRNAs are deregulated early in T1D patients who are at risk for rapid progression to ESRD.

Figure 1

Relative levels of TGF-β1–regulated miRNAs in plasma from rapid progressors, nonprogressors, and normoalbuminuric control subjects. The relative levels of let-7b-5p, let-7c-5p, miR-21-5p, miR-29a-3p, and miR-29c-3p were significantly different among patients with proteinuria who either lost (i.e., rapid progressors) or maintained (i.e., nonprogressors) renal function over the follow-up period and normoalbuminuric control subjects (Kruskal-Wallis P ≤ 0.0003) (Table 3). miR-192-5p levels were similar among all patients examined in this study (Kruskal-Wallis P = 0.15) (Table 3). Mann-Whitney U test P values from comparisons between rapid progressors and nonprogressors are provided. Horizontal bars indicate the median (bold) and first and third quartile in each group. Normalized relative levels of each miRNA are presented in the form 2^−ΔCq, and cel-miR-39-3p was used as a stable reference normalization control. NA, normoalbuminuric control subjects; NP, nonprogressors; RP, rapid progressors.