Abstract
Excessive transforming growth factor-beta (TGF-beta) activity in hyperglycemia contributes to the development of diabetic nephropathy. Glucose stimulation of TGF-beta activity and matrix synthesis are dependent on autocrine thrombospondin 1 (TSP1) to convert latent TGF-beta to its biologically active form. The mechanisms by which glucose regulates TSP1 are not known. High glucose inhibits nitric oxide (NO) bioavailability and decreased NO increases TGF-beta activity and extracellular matrix accumulation. Yet, the impact of NO signaling on TSP1 activation of TGF-beta is unknown. We tested the role of NO signaling in the regulation of TSP1 expression and TSP1-dependent TGF-beta activity in rat mesangial cells exposed to high glucose. On exposure to 30 mm glucose, NO accumulation in the conditioned media and intracellular cGMP levels were significantly decreased. The addition of an NO donor prevented the glucose-dependent increase in TSP1 mRNA, protein, and TGF-beta bioactivity. The effects of the NO donor were blocked by ODQ (a soluble guanylate cyclase inhibitor) or Rp-8-pCPT-cGMPS (an inhibitor of cGMP-dependent protein kinase). These effects of high glucose were also reversed by the nitric-oxide synthase cofactor tetrahyrobiopterin (BH(4)). These results show that high glucose mediates increases in TSP1 expression and TSP1-dependent TGF-beta bioactivity through down-modulation of NO-cGMP-dependent protein kinase signaling.
Highlights
Hyperglycemia is a crucial factor in the development of diabetic renal complications, with multiple lines of evidence suggesting that high glucose stimulates an increase in transforming growth factor- (TGF-)1 activity [1,2,3]
These data suggest that the NOsignaling pathway at the level of either nitric oxide (NO) production or bioavailability is decreased on acute exposure of mesangial cells to media containing high glucose
Data presented in this study show decreased NO and cGMP levels in RMCs in response to high glucose
Summary
Normal glucose High glucose Normal glucose with Deta (5 M) High glucose with Deta (5 M). A decrease in endogenous NOS activity appears to play a role since basal levels of TSP1 and TGF- activity can be restored by the NOS co-factor BH4. These effects of exogenous NO in the high glucose media are blocked by both an inhibitor of soluble guanylate cyclase and a selective inhibitor of PKG. These data provide the first evidence that NO-dependent PKG activity is involved in the regulation of TSP1 expression and TGF- bioactivity in response to high glucose concentrations
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