Abstract
Diabetic Nephropathy (DN) is a chronic complication of diabetes and the primary cause of end stage renal disease. Differential diagnosis for DN requires invasive histological investigation, thus there is need for non-invasive biomarkers to discriminate among different histological lesions in diabetic patients. With the aim to identify a pattern of differentially expressed miRNAs in kidney biopsies of DN patients, we assayed miRNA expression in kidney biopsies from DN patients, diabetic patients with membranous nephropathy and patients with normal histology. Nine miRNAs were differentially expressed among the three groups, and 2 miRNAs (miR-27b-3p and miR-1228-3p) showed interaction with an ubiquitin-conjugating E2 enzyme variant (UBE2v1). UBE2v1 mediates the formation of lysine 63-linked ubiquitin chains, a mechanism we previously showed as involved in DN kidney fibrosis. Both miRNAs were validated as down-regulated in biopsies and urines of DN patients, possibly affected by DNA methylation. Interestingly, the urinary levels of both miRNAs could also discriminate among different degrees of renal fibrosis. Finally, we showed that the combined urinary expression of both miRNAs was also able to discriminate DN patients from other glomerulonephritides in diabetic patients. In conclusion we identified two miRNAs potentially useful as candidate biomarkers of tubular-interstitial fibrosis in diabetic patients with DN.
Highlights
Epidemiological studies show that one third of patients with DM develops diabetic nephropathy (DN) while other diabetic patients develop a non-diabetic renal disease (NDRD) such as membranous nephropathy (MN), IgA nephropathy, focal segmental glomerulosclerosis (FSGF), etc
In order to evaluate whether diabetic kidney damage is characterized by different miRNA profiles, we performed an array-based miRNome profiling on total RNA extracted from 6 Diabetic Nephropathy (DN), 6 T2D-MN, and 4 normal kidney morphology (NK) kidney biopsy tissues
By applying a fold change = 1.5, FDR ≤ 0.05, we identified 61 miRNAs differentially expressed in DN when compared to NK, 41 miRNAs differentially expressed in DN when compared to T2D-MN and 45 miRNAs differentially expressed in T2D-MN when compared to NK (Fig. 1B and Supplementary Table S1)
Summary
Epidemiological studies show that one third of patients with DM develops diabetic nephropathy (DN) while other diabetic patients develop a non-diabetic renal disease (NDRD) such as membranous nephropathy (MN), IgA nephropathy, focal segmental glomerulosclerosis (FSGF), etc. DN is routinely diagnosed on the basis of clinical findings such as albuminuria, ranging from micro- (30–300 mg/d) to macro-albuminuria (≥300 mg/d), and reduced glomerular filtration rate These signs per se are not distinctive of DN as they occur in patients with different forms of renal damage. There is an urgent need for specific, rapid, non-invasive and inexpensive biomarkers to discriminate NDRD from DN forms; this would help clinicians in making an accurate diagnosis and set the most appropriate therapy[9]. In this scenario, microRNA may represent ideal candidate biomarkers[10]. The tissue expression of miRNAs in diabetic kidney samples with different histological damage, such as non-diabetic lesions in diabetic patients, has not yet been investigated
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