Chronic progressive interstitial fibrosis in renal disease—are there novel pharmacological approaches? (1999)

AT1 receptor antagonists improve capillary hyperIntroduction tension of the glomerulus via reduction of glomerular efferent arteriolar tone. Thus they interfere with the Progressive loss of renal function is associated not only development of glomerular injury and proteinuria [3]. with development of glomerulosclerosis, but also with In addition, disturbed glomerular barrier function secthat of interstitial fibrosis. Interstitial fibrosis is characondary to activation of AT1 receptor by AII permits terized by the destruction of renal tubules and interproteins to escape into the urinary space and to exert stitial capillaries as well as by the accumulation of toxic effects upon tubular epithelial cells [1,7]. Immune extracellular matrix proteins. The severity of tubuloinresponses of tubular epithelial cells are induced by terstitial fibrosis has long been considered as a crucial exposure to proteins, e.g. stimulation of the release of determinant of progressive renal injury in both human various cytokines, including transforming growth and experimental glomerulonephritis. Moreover, previ1 1 [1]. The release of such cytokines ous studies have shown that decrease in glomerular causes differentiation of interstitial fibroblasts (and filtration rate is better correlated with tubulointerstitial possibly tubular epithelial cells) into myofibroblasts. injury than with glomerulosclerosis [1,2]. This change of phenotype is characterized by de novo Many studies have been published on the mechanisms and treatment of glomerulosclerosis. In contrast, expression of alpha-smooth-muscle actin [8]. Recently, the pathogenesis of interstitial fibrosis has been less a specific gene (Fsp1) [9,10] was cloned, which triggers well understood. The mechanisms that contribute to the transformation of tubular epithelial cells into these two types of matrix accumulation in the kidney myofibroblasts [11] in response to cytokines, such as are in part common, but to some extent also different. TGF-b. Furthermore, it has been shown that AII In this brief editorial, we focus on some new directly induced the expression of TGF-b in cultured approaches to interstitial fibrosis that have recently renal tubular cells and in fibroblasts [12]. Taken helped to elucidate its pathogenesis. together, the activation of AT1 receptors in glomeruli, tubular epithelial cells and interstitial fibroblasts might be involved in the progression of interstitial fibrosis. New roles of the renin–angiotensin system in the In the rat remnant kidney model, an AT1 receptor development of interstitial fibrosis antagonist, candesartan cilexetil (TCV-116), was superior in preventing interstitial fibrosis and glomRecent reports suggest that angiotensin II (AII ) plays erulosclerosis compared to angiotensin-converting important roles in the development and amelioration enzyme inhibitor (ACI) [13]. The beneficial effects of of interstitial fibrosis through different types of AII AT1 receptor antagonist were initially thought to be receptors. AII not only contributes to glomerular capilmediated mainly by the blockade of AT1 receptors. lary hypertension and an impairment of glomerular In contrast to the AT1 receptor, much less is known permselectivity, but influences also directly some funcabout the functional properties of AT2 receptor. Since tions of interstitial fibroblasts and tubular epithelial AT2 receptor expression is high in embryonic tissues cells [3,4]. To date, molecular cloning and pharmacoand declines dramatically after birth [14], it was postulogical studies have defined two major classes of AII lated that the AT2 receptor played a role in cell growth receptors, i.e. AT1 and AT2 receptors. Most known and differentiation. In contrast, recent reports sugeffects of AII are mediated by AT1 receptors [5,6 ]. gested that AT2 receptors mediate antiproliferative effects and participate in cell apoptosis [5,6 ]. Since AII Correspondence and offprint requests to: Masafumi Fukagawa MD exhibits growth promoting properties via AT1 receptor PhD, Division of Nephrology and Clinical Research Center, Tokyo in some cell types, AT1 and AT2 receptors might Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan. mediate counterbalancing signals [15]. A similar recip-