Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of ESKD in Diabetes

Abstract

Background Mechanisms underlying the progression of diabetic kidney disease to end-stage kidney disease (ESKD) are not fully understood. Methods We performed global micro-RNA (miRNA) analysis in plasma in two cohorts encompassing 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease and targeted proteomics analysis in plasma in four cohorts encompassing 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsies from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. Results In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, miR-328-3p), which were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins—most notably EFNA4 and EPHA2—were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsies. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. Conclusions This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.

Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes

“…In addition, the NRI methodology was applied for categorical risk estimates. Risk categories for ESKD during 10 years were defined by <5.0%, 5.0 to 9.9%, 10.0 to 19.9%, and 20% and more (64,96)…”

“…The SOMAscan measurements were used to examine 25 prespecified circulating proteins modulating TGF-β signaling as predictors for progression to ESKD. This targeted approach was used in our recent studies ( 62 – 64 ). In this study, we identified increased concentration of neuroblastoma suppressor of tumorigenicity 1 (NBL1; aliases DAN and DAND1), a presumed inhibitor of BMP proteins, as a strong and independent predictor of progression to ESKD in all study cohorts ( 65 – 71 ).…”

Icariin and Competing Endogenous RNA Network: A Potential Protective Strategy Against Contrast-Induced Acute Kidney Injury

“…MiR-339-5p was proven to be associated with risk of end stage kidney disease in diabetic patients. 27 In glomerular mesangial cells, miR-146b-5p attenuated the inflammatory response by inhibiting Toll-like receptor 4 pathway in lupus nephritis. 28 MiR-345-3p also presented significant pathological relevance in cardiorenal syndrome.…”

The Non-Coding RNA Journal Club: Highlights on Recent Papers—10

“…A key objective—because not all diabetic patients progress identically—is the early prediction of diabetic kidney disease (DKD). To address this unmet need, the study has assessed the expression of circulating miRNAs and proteins in peripheral blood from individuals with DKD (type 1 and type 2 diabetes) from the Joslin Kidney Study (88% of European–American ancestry) and the Pima Indian Kidney Study (100% of Indigenous–American ancestry) [ 1 ]. Statistically, 17 miRNAs were found to be significant and differentially expressed, pointing towards networks that influence the Axonal Guidance Pathway (AGP) and Ras signaling.…”