kmup-1 and Fibrosis

We have previously demonstrated that KMUP-1, a xanthine-based nitric oxide enhancer, attenuates diabetic glomerulosclerosis, while increasing renal endothelial nitric oxide synthase expression in rats. However, the anti‑fibrotic mechanisms of KMUP‑1 treatment in diabetic nephropathy in terms of cell biology and transforming growth factor-β1 (TGF‑β1) remain unclear. Therefore, the present study involved investigating the effects of KMUP‑1 on high glucose (HG) or TGF‑β1‑induced pro‑fibrotic proteins in mouse mesangial (MES13) cells, and the effects of KMUP‑1 on streptozotocin (STZ)‑induced diabetic rats. It was identified that KMUP‑1 (10 µM) attenuated HG (30 mM)‑induced cell hypertrophy while attenuating TGF‑β1 gene transcription and bioactivity in MES13 cells. In addition, KMUP‑1 attenuated TGF‑β1 (5 ng/ml)‑induced Smad2/3 phosphorylation while attenuating HG or TGF‑β1‑induced collagen IV and fibronectin protein expression. Furthermore, KMUP‑1 attenuated HG‑decreased Suv39h1 and H3K9me3 levels. Finally, KMUP‑1 attenuated diabetes-induced collagen IV and fibronectin protein expression in STZ‑diabetic rats at 8 weeks. In conclusion, KMUP‑1 attenuates HG and TGF‑β1‑induced pro‑fibrotic proteins in mesangial cells and attenuation of TGF‑β1‑induced signaling and attenuation of HG‑decreased Suv39h1 expression may be two of the anti-fibrotic mechanisms of KMUP‑1.

Topics: Animals; Cell Line; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibronectins; Fibrosis; Glucose; Histones; Mesangial Cells; Methyltransferases; Mice; Piperidines; Signal Transduction; Smad2 Protein; Smad3 Protein; Streptozocin; Transforming Growth Factor beta1; Xanthines

To determine whether KMUP-1, a novel xanthine-based derivative, attenuates isoprenaline (ISO)-induced cardiac hypertrophy in rats, and if so, whether the anti-hypertrophic effect is mediated by the nitric oxide (NO) pathway.. In vivo, cardiac hypertrophy was induced by injection of ISO (5 mg.kg(-1).day(-1), s.c.) for 10 days in Wistar rats. In the treatment group, KMUP-1 was administered 1 h before ISO. After 10 days, effects of KMUP-1 on survival, cardiac hypertrophy and fibrosis, the NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) and hypertrophy signalling pathways [calcineurin A and extracellular signal-regulated kinase (ERK)1/2] were examined. To investigate the role of nitric oxide synthase (NOS) in the effects of KMUP-1, a NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA) was co-administered with KMUP-1. In vitro, anti-hypertrophic effects of KMUP-1 were studied in ISO-induced hypertrophic neonatal rat cardiomyocytes.. In vivo, KMUP-1 pretreatment attenuated the cardiac hypertrophy and fibrosis and improved the survival of ISO-treated rats. Plasma NOx (nitrite and nitrate) and cardiac endothelial NOS, cGMP and PKG were all increased by KMUP-1. The activation of hypertrophic signalling by calcineurin A and ERK1/2 in ISO-treated rats was also attenuated by KMUP-1. All these effects of KMUP-1 were inhibited by simultaneous administration of L-NNA. Similarly, in vitro, KMUP-1 attenuated hypertrophic responses and signalling induced by ISO in neonatal rat cardiomyocytes.. KMUP-1 attenuates the cardiac hypertrophy in rats induced by administration of ISO. These effects are mediated, at least in part, by NOS activation. This novel agent, which targets the NO/cGMP pathway, has a potential role in the prevention of cardiac hypertrophy.

Topics: Animals; Calcineurin; Cardiomegaly; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Drug Delivery Systems; Fibrosis; Isoproterenol; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitric Oxide; Nitric Oxide Synthase; Piperidines; Rats; Rats, Wistar; Signal Transduction; Survival Rate; Xanthines