Nitric oxide increases albumin permeability of isolated rat glomeruli via a phosphorylation-dependent mechanism.
Nitric oxide (NO) has been implicated in the induction of proteinuria in acute inflammatory glomerulonephritis and in the increased vascular permeability seen in various other disease conditions. The complicated interactions of NO with other factors in vivo hinder analysis of the mechanisms involved. By use of a recently introduced method for measuring albumin permeability (P(a)) in isolated glomeruli, the question of whether NO has a direct effect on the permeability barrier of glomerular tufts was examined and the potential mechanisms were explored. Exposure of isolated glomeruli to three NO donors, s-nitroso-N-acetyl-penicillamine (SNAP), (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate), and sodium nitroprusside, all increased the P(a). This action of NO was time- and concentration-dependent and could be mimicked by 8-bromoguanosine 3', 5'-cyclic monophosphate. Western blot analysis of the proteins from NO donor-treated glomeruli revealed an increase of phosphotyrosine levels of proteins of molecular mass about 120 and 70 kD. The demonstration that pretreatment of glomeruli with the tyrosine kinase inhibitor, genistein, could largely prevent the effect of SNAP and DETA-NONOate confirmed the crucial role of tyrosine phosphorylation in the NO-induced increase of P(a). Furthermore, the tyrosine phosphatase inhibitor, phenylarsine oxide (PAO), could mimic the action of NO on P(a). NO-enhanced tyrosine phosphorylation was further confirmed by immunofluorescence staining, where positive cells in SNAP- and PAO-treated glomeruli were much more frequent than that in controls. By use of dual-label staining in combination with podocyte specific marker, nephrin, it was observed that most of the phosphorylated positive cells corresponded to podocytes. These results suggest that NO impairs the glomerular permeability barrier through a tyrosine phosphorylation-dependent mechanism.[1]References
- Nitric oxide increases albumin permeability of isolated rat glomeruli via a phosphorylation-dependent mechanism. Li, B., Yao, J., Morioka, T., Oite, T. J. Am. Soc. Nephrol. (2001) [Pubmed]
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