Global Analysis of Glucose-Stimulated Gene Expression Identifies Tenascin-C as a Relevant Player in Diabetic Nephropathy

Abstract

Diabetic nephropathy results from excess accumulation of the mesangial extracellular matrix (ECM), which can cause end-stage kidney disease. Pathological conditions within the diabetic kidney—high glucose and the presence of advanced glycation end products (AGEs)—have been shown to increase assembly of extracellular fibronectin (FN) matrix, a key organizer of the mesangial ECM. The role of high glucose and AGEs on gene expression of ECM genes, however, is poorly understood. We performed RNA-Seq using a mesangial cell model with differing glucose and AGE conditions. Strikingly, the second and third most up-regulated pathways in high glucose are ECM-related. While we did not observe a change in FN gene expression, expression of another ECM protein, tenascin-C (TN-C), was increased more than 3-fold. Analysis of TN-C revealed that high glucose promotes selective expression of a large isoform, whereas a smaller isoform is prominent in normal glucose. The small isoform is incorporated into matrix, while the large is not. Genetically engineered small and large isoforms of TN-C show a similar pattern, and suggest that only the small isoform is capable of interacting with the FN matrix. Overall, our study provides insights into the mesangial cell response in diabetic conditions and identifies TN-C, specifically the small isoform, as a potential regulator of mesangial ECM expansion.