Adenosine 3′, 5′ cyclic monophosphate attenuates the production of fibronectin in the glomeruli of anti‐glomerular basement membrane antibody‐associated nephritic rats

Abstract

1 Excessive production of extracellular matrix is thought to be involved in the progression of glomerulonephritis and glomerulosclerosis. In chronic glomerulonephritis, fibronectin has been shown to accumulate in the glomeruli, accompanied by cell proliferation. 2 Glomerulonephritis was induced in rats by the injection of anti-glomerular basement membrane antibody. The rats showed proteinuria and histological alterations in the glomeruli. An increase in fibronectin levels in the culture medium of isolated nephritic glomeruli was confirmed, and was associated with the development of nephritis. Immunohistochemical staining demonstrated a marked accumulation of fibronectin in the glomeruli of nephritic rats. 3 Attenuated generation of cyclic AMP was also observed in the nephritic glomeruli treated with forskolin, prostaglandin E1 or adenosine. 4 Forskolin, prostaglandin E2 and 8-bromo-cyclic AMP markedly reduced the production of fibronectin by the nephritic glomeruli compared with controls in a dose-dependent manner. 8-Bromocyclic AMP suppressed the production of fibronectin by cultured mesangial cells. 5 These findings suggest that the attenuated generation of cyclic AMP in response to ligands is connected to the augmented accumulation of fibronectin in nephritic glomeruli, and may facilitate the development of methods for treating glomerulonephritis and glomerulosclerosis.

Protective Effect of Prostaglandin EP4-Receptor Agonist on Anti-glomerular Basement Membrane Antibody-Associated Nephritis

“…1B). The present findings are consistent with the previous reports using the glomeruli isolated from anti-glomerular basement membrane nephritic rats (10). Both EP 2 and EP 4 receptors are coupled with Gs protein in the cell membrane and generate cyclic AMP (21).…”

“…1C). Cyclic AMP suppresses the excessive production of fibronectin in rat nephritic glomeruli (10) and recovers the function of injured spinal cord (23). Hence, we performed experiments to elucidate the anti-nephritic effect of an EP 4 -receptor agonist in the development of anti-glomerulus antibody-associated nephritis.…”

“…The glomeruli produce prostaglandin E 2 in the basal condition and generate cyclic AMP in response to prostaglandin E 2 (7,9). Prostaglandin E 2 , cyclic AMP analogues, and cyclic AMP-elevating agents exert various effects, including reducing excessive fibronectin production and increasing disposal of aggregated protein, on the glomeruli and mesangial cells (10,11). The aim of this study was to elucidate 1) how much cyclic AMP is generated in the glomeruli from nephritic mice induced by anti-glomerulus antiserum, 2) whether the expression of EP receptor mRNA in the glomeruli is affected by induction of glomerulonephritis, and 3) whether an EP 4 agonist retards the development of glomerulonephritis.…”

Involvement of Protein Kinase C in Reduction of Aggregated Protein and Phosphorylation of CREB in Glomeruli

“…Prostaglandin e 2 stimulates production of cyclic amP via eP2 and eP4 prostaglandin e receptors in isolated glomeruli [6,7,14]. we have demonstrated that isolated glomeruli generate prostaglandin e 2 and that a-Bsa increases the expression of cyclooxygenase-2 mrNa and cyclooxygenase-2 activity followed by the expression of prostaglandin e 2 [5].…”

“…The glomeruli were isolated with two kinds of nylon mesh (90-and 38-mm) and a magnet [7]. The purity of the glomeruli was more than 95% as observed under a light microscope.…”