SUPPRESSION OF MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS DEVELOPMENTIN RATS BY INHIBITORS OF CAMP-PHOSPHODIESTERASE ISOZYMES TYPE-II AND TYPE-IV

Excessive mesangial cell (MC) proliferation is a hallmark of many glom erulopathies. In our recent study on cultured rat MC (Matousovic, K., J.P. Grande, C,C,S. Chini, E.N. Chini, and T.P. Dousa. 1995. J. Clin. Invest. 96:401-410) we found that inhibition of isozyme cyclic-3',5'-n ucleotide phosphodiesterase (PDE) type III (PDE-III) suppressed MC mit ogenesis by activating cAMP-dependent protein kinase (PKA) and by decr easing activity of mitogen-activated protein kinase (MAPK). We also fo und that inhibition of another PDE isozyme, PDE-IV, suppresses superox ide generation in glomeruli (Chini, C.C.S., E,N. Chini, J,M, Williams, K, Matousovic, and T.P. Dousa, 1994, Kidney Int. 46:28-36). We thus e xplored whether administration in vivo of the selective PDE-III antago nist, lixazinone (LX), together with the specific PDE-IV antagonist, r olipram (RP), can attenuate development of mesangioproliferative glome rulonephritis (MSGN) induced in rats by anti-rat thymocyte serum (ATS) , Unlike the vehicle-treated MSGN rats, rats with MSGN treated with LX and RP did not develop proteinuria and maintained normal renal functi on when examined 5 d after injection of ATS. In PAS-stained kidneys fr om PDE-antagonists-treated MSGN-rats the morphology of glomeruli showe d a reduction in cellularity compared with control rats with ATS. Comp ared with MSGN rats receiving vehicle, the MSGN rats receiving PDE-ant agonists had less glomerular cell proliferation (PCNA delta -65%), a s ignificantly lesser macrophage infiltration (delta -36% ED-1) and a si gnificant reduction of a-smooth muscle actin expression by activated M C; in contrast, immunostaining for platelet antigens and laminin were not different. The beneficial effect of PDE inhibitors was not due to a moderate decrease (similar to -20%) in systolic blood pressure (SEP) ; as a similar decrease in SEP due to administration of hydralazine, a drug devoid of PDE inhibitory effect, did not reduce severity of MSGN in ATS-injected rats. We conclude that antagonists of PDE-III and PDE -IV administered in submicromolar concentrations in vivo to ATS-inject ed rats can decrease the activation and proliferation of MC, inhibit t he macrophage accumulation, and prevent proteinuria in the acute phase of MSGN. We propose that PDE isozyme inhibitors act to block (negativ e ''crosstalk'') the mitogen-stimulated intracellular signaling pathwa y which controls MC proliferation due to activating of the cAMP-PKA pa thway, These results suggest that antagonists of PDE-III and IV may ha ve a suppressive effect in acute phases or relapses of glomerulopathie s associated with MC proliferation.