Role of endothelin as a mitogen in experimental glomerulonephritis in rats

Abstract

Recent studies have revealed that endothelin-1 (ET-1) is a potent mitogen for mesangial cells in vitro. To determine whether ET-1 exerts the mitogenic action on mesangial cells in vivo, we examined the glomerular expression of ET-1 and its receptors in a rat model of mesangial proliferative glomerulonephritis and assessed the effect of a specific endothelin A (ET(A)) receptor antagonist, FR139317, on mesangial cell proliferation in this model. The levels of preproET-1 mRNA expression and ET-1 protein production in glomeruli increased markedly on days 4 and 7 after disease induction, and the levels changed in concordance with the glomerular cell proliferation. In contrast, the level of ET(A) receptor mRNA initially decreased on day 1, and thereafter increased on days 4 and 7. Administration of FR139317 to rats with experimental glomerulonephritis induced a significant reduction in mesangial cell proliferation. In addition, in situ hybridization of preproET-1 mRNA and double-immunolabeling of ED-1 and OX-7 in a mirror image section revealed that the principal cell expressing ET-1 in glomeruli were infiltrating macrophages on day 1, and they were replaced by mesangial cells on day 4. These findings indicate that ET-1 functions as a potent mitogen for mesangial cells in vivo in an autocrine or paracrine fashion.

Nephroprotection of an ET A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

“…28 The inhibitory effect of ET A receptor blockade on the development of glomerulosclerosis and of interstitial or vascular lesions appears plausible in view of the known renal actions of ET-1, ie, mitogenic effects on mesangial cells 29,30 and increased expression of fibronectin and collagen. 7,31 Furthermore, ET-1 stimulates the production of cytokines such as platelet-derived growth factor. 30 In the rat kidney, ET A receptors have been demonstrated in mesangial cells and ET B receptors in endothelial and epithelial cells.…”

“…3 In rats with renal ablation, ET A as well as mixed ET A/B receptor antagonists reduced glomerulosclerosis and proteinuria. 4,5 Nephroprotective effects of ET receptor antagonists have also been reported in other models of renal damage, ie, lupus nephritis, 6 mesangioproliferative nephritis, 7 and diabetes. 8 Inhibition of progression of renal failure may emerge as an important indication for ET receptor antagonists.…”

Distribution of Endothelin Receptor Subtypes ETA and ETB in the Rat Kidney

“…Renal effects of ET-1 have been ascribed to both receptor subtypes by the use of non-selective and selective ET receptor agonists and antagonists. In the rat, proliferative effects of ET-1 on mesangial cells are mediated by the ET A receptor subtype (Fukuda et al 1996), and stimulation of ET B receptors inhibits sodium and water reabsorption (Watanabe et al 1991;Gariepy et al 2000). ET A as well as ET B receptors are involved in the regulation of renal vascular resistance.…”

Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction

“…ET-1 induces mesangial cell proliferation (15,20,72), and expression of the predominant extracellular protein collagen IV is mediated in part through PKC and activation of ERK1/2 (22). ET-1 signals through G-protein coupled receptor (GPCR)-mediated PLC hydrolysis of phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate and diacylglycerol, releasing Ca 2ϩ and activating PKC, respectively (11,49).…”