Tetrahydrobiopterin contributes to the proliferation of mesangial cells and accumulation of extracellular matrix in early-stage diabetic nephropathy

Abstract

Abstract Objectives Nitric oxide (NO) plays an important role in the progression of early-stage diabetic nephropathy (DN), which is found to contribute to extracellular matrix (ECM) accumulation in mesangial cells (MCs). As a cofactor for NO production, tetrahydrobiopterin (BH4), a folacin analogue, may be responsible for the ECM accumulation and proliferation of MCs. This study was to investigate the effects of BH4 on glomerulosclerosis in early-stage DN. Methods In in vitro studies with cultured mesangial cells and in vivo studies with streptozotocin-induced diabetic rats, BH4 levels were assayed by HPLC; NO was determined by Griess agents; laminin and collagen IV were determined by enzyme-linked immunosorbent assay; the inducible NO synthase protein was determined by immunofluorescence staining and Western blot; and mesangial matrix expansion and MC proliferation in the renal cortex were observed by periodic acid–schiff staining and transmission electron microscopy, respectively. Key findings The in vivo and in vitro studies indicated that the increased BH4 resulted in the overproduction of NO, ECM accumulation and the proliferation of MCs in early-stage DN. Conclusions Our results suggest that inhibiting excessive BH4 may be a potential approach to prevent glomerulosclerosis in early-stage DN.