sepiapterin and Diabetic-Nephropathies

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in DN. Elimination of tetrahydrobiopterin (BH(4)) and nitric oxide (NO) bioavailability may contribute to the aggravation of DN. The present study aims to explore any possible beneficial effect of exogenous BH(4) in alleviating the AGE-induced renal tubular hypertrophy in DN. Thus, renal tubular cells were treated with BH(4), BH(2), sepiapterin, or DAHP in the presence of AGE. We found that AGE (but not non-glycated BSA) markedly reduced NO production and increased hypertrophy index in these cells. Exogenous BH(4)/BH(2) and sepiapterin treatments attenuated AGE-inhibited the iNOS/NO/GTPCH I protein synthesis. Moreover, BH(4) and BH(2) significantly reversed AGE-enhanced the JAK2-STAT1/STAT3 activation. The abilities of BH(4) and BH(2) to inhibit AGE-induced renal cellular hypertrophy were verified by the observation that BH(4) and BH(2) inhibited hypertrophic growth and the protein synthesis of p27(Kip1) and α-SMA. These findings indicate for the first time that exogenous BH(4) and BH(2) attenuate AGE-induced hypertrophic effect at least partly by increasing the iNOS/GTPCH I synthesis and NO generation in renal tubular cells.

Topics: Actins; Biopterins; Cell Enlargement; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27; Diabetic Nephropathies; Gene Expression Regulation; Glycation End Products, Advanced; GTP Cyclohydrolase; Humans; Janus Kinase 2; Kidney Tubules; Nitric Oxide; Nitric Oxide Synthase Type II; Pterins; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Sugar Acids

Impaired endothelial nitric oxide synthase (eNOS) activity may be involved in the pathogenesis of diabetic nephropathy. To test this, we used the type 2 diabetic db/db mouse (BKS background) model and found impaired eNOS dimerization and phosphorylation along with moderate glomerular mesangial expansion and increased glomerular basement membrane (GBM) thickness at 34 weeks of age. Cultured murine glomerular endothelial cells exposed to high glucose had similar alterations in eNOS dimerization and phosphorylation. Treatment with sepiapterin, a stable precursor of the eNOS cofactor tetrahydrobiopterin, or the nitric oxide precursor L-arginine corrected changes in eNOS dimerization and phosphorylation, corrected permeability defects, and reduced apoptosis. Sepiapterin or L-arginine, administered to db/db mice from weeks 26 to 34, did not significantly alter hyperfiltration or affect mesangial expansion, but reduced albuminuria and GBM thickness, and decreased urinary isoprostane and nitrotyrosine excretion (markers of oxidative stress). Although there was no change in glomerular eNOS monomer expression, both sepiapterin and L-arginine partially reversed the defect in eNOS dimerization and phosphorylation. Hence, our results support an important role for eNOS dysfunction in diabetes and suggest that sepiapterin supplementation might have therapeutic potential in diabetic nephropathy.

Topics: Animals; Arginine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Endothelium, Vascular; Glucose; Kidney Glomerulus; Mice; Nitric Oxide Synthase Type III; Pterins