Reciprocal functions of hepatocyte growth factor and transforming growth factor-beta1 in the progression of renal diseases: a role for CD44?
Progressive renal fibrosis occurs via common pathophysiologic mechanisms, regardless of the primary underlying disease. This cascade includes release of cytokines/chemokines and toxic molecules, interstitial inflammation, tubular cell damage, accumulation of myofibroblasts, and finally, fibrosis. Hepatocyte growth factor (HGF) and transforming growth factor-beta1 (TGF-beta1) are key molecules in this cascade that, in general, exert opposite actions. Hepatocyte growth factor promotes, to some extent, inflammation, protects tubular epithelial cells, blocks myofibroblast transition, and contributes to tissue remodeling. In contrast, TGF-beta1 has powerful anti-inflammatory actions, promotes apoptosis, induces myofibroblast transition, and is a strong pro-fibrotic agent. The mechanisms which orchestrate the reciprocal actions of HGF and TGF-beta1 are still largely unknown and are probably multiple. One of these mechanisms involves the selective up-regulation of CD44 in damaged kidney. The glomerular and tubular expression of CD44 closely correlates with the degree of renal damage, and CD44 has been shown to facilitate the action of both HGF and TGF-beta1. Moreover, during chronic obstructive nephropathy CD44 knock-out mice display much more tubular damage but develop less fibrosis in the course of the renal disease. These histologic findings are associated with impairment of signaling pathways of both HGF and TGF-beta1. The development of new therapeutic strategies aimed at preventing progression of renal diseases that are based on HGF and/or TGF-beta1 may take in account the pivotal role of CD44 expression in the functions of both molecules.
Florquin
Sandrine
S
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands. s.Florquin@amc.uva.nl
Rouschop
Kasper M A
KM
D000818:Animals; D018450:Disease Progression; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007674:Kidney Diseases / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D018960:Hyaluronan Receptors; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor