MODULATORY EFFECTS OF EICOSANOIDS ON MESANGIAL CELL-GROWTH IN RESPONSE TO IMMUNE INJURY

In a rat model of glomerular mesangial cell immune injury induced by a monoclonal antibody (ER(4)) against the mesangial cell membrane antig en Thy 1.1 and in which mesangial cell proliferation is a prominent fe ature, we examined the role of arachidonate 5- and 12-lipoxygenation ( LO) eicosanoids and of thromboxane (Tx) in modulating the proliferativ e response. Significant increments in glomerular cell proliferation, a ssessed by counting glomerular cells positive for the Proliferating Ce ll Nuclear Antigen (PCNA) and by the incorporation of [H-3]thymidine ( [H-3]TdR) in mesangial cell outgrowths from explanted glomeruli, occur red during the mesangioproliferative phase of injury. This event was a brogated in animals depleted of leukocytes or platelets prior to admin istration of ER(4) and in animals pretreated with the arachidonate 5-L O inhibitor MK886. Pretreatment with the Tx synthase inhibitor, Furegr elate, or the arachidonate 12-LO inhibitor, Baicalein, had no effect, indicating that eicosanoids of arachidonate 5-LO but not those of 12-L O or Tx modulate mesangial cell proliferation following immune injury. We further identified those 5-lipoxygenation eicosanoids with growth modulatory effects on cultured mesangial cells. Leukotriene (LT)C-4 an d D-4 but not LTB(4), or 5-hydroxyeicosatetraenoic (HETE) acid enhance d [H-3]TdR incorporation in growth-arrested mesangial cells. This effe ct of LTC(4) and LTD(4) was abrogated by the specific protein kinase C (PKC) inhibitor calphostin C, indicating a PKC-dependent mechanism. L TC(4) and LTD(4) but not 5-HETE or LTB(4) also increased mesangial cel l mass levels of the endogenous PKC activator diacylglycerol. The obse rvations indicate that leukocyte-derived arachidonate 5-LO eicosanoids modulate mesangial cell proliferation following immune injury. Of the se LTC(4) and LTD(4) are the likely candidates as they promote mesangi al cell growth via a PKC-dependent mechanisms.