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

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.

Keywords: diabetic nephropathy; extracellular matrix; nitric oxide; proliferation; tetrahydrobiopterin.