title: Macrophages and progressive renal disease in experimental hydronephrosis.
abstract: Many recent clinical and experimental studies have clearly demonstrated that one of the initial events taking place in the process of progressive renal injury is monocytic infiltration of the glomerular and tubulointerstitial compartments. In this report, experimental data supporting the role of the infiltrating renal macrophage (M phi) as a mediator of interstitial fibrosis during the course of obstructive nephropathy will be reviewed as it pertains to the unilateral ureteral obstruction model in the rat. The central pathobiologic theme drawn on data from this model is that fibrogenic cytokines, especially transforming growth factor-beta, are, in part, M phi-derived and represent pivotal links between the initial postobstructive renal inflammation and the late development of renal scarring. The tubular epithelium, as a consequence of the mechanical disturbance produced by ureteral obstruction, may elaborate a host of M phi chemoattractant moieties. Many substances can be released by these infiltrating M phi; however, our studies have focused on transforming growth factor-beta 1. Transforming growth factor-beta is an important regulator of extracellular matrix, through its direct effects and modulation of other growth factors to maintain matrix homeostasis. We propose that the markedly increased expression of transforming growth factor-beta 1 following ureteral ligation, as detected by a number of laboratories, induces a profibrogenic state and initiates a cascade of dysregulatory events, including the upregulation of tissue inhibitors of metalloproteinase. Transforming growth factor-beta 1 also may serve as a potent stimulus for the modulation of quiescent interstitial fibroblasts into myofibroblasts. From a therapeutic standpoint, targeting these early cellular and molecular events may be extremely important in interrupting the interstitial fibrotic response to long-term obstructive uropathy.
authors.affiliation: Department of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Diamond
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000209:etiology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D006023:Glycoproteins / Q000378:metabolism; D006869:Hydronephrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology; D008026:Ligation; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051381:Rats; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014513:Ureter
chemical_list: D006023:Glycoproteins; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D008666:Metalloendopeptidases