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Hierarchy of molecules in TGF-β1 signaling relevant to myofibroblast activation and renal fibrosis.

A NUMBER OF MOLECULES using different transforming growth factor (TGF)-1-induced signaling pathways are involved that activate a wide variety of cells leading to a terminal event known as “scarring or fibrosis” in various organ systems. Likewise, renal fibrosis is an inevitable consequence of various types of progressive chronic kidney diseases (CKD), and it is characterized by continued exacerbation of glomerulosclerosis, tubular atrophy, and interstitial fibrosis, which leads to irreversible kidney scarring. In the clinical setting, CKD patients with recalcitrant renal fibrosis manifest with progressive renal function loss, and they ultimately develop end-stage renal disease (ESRD), which requires renal replacement therapy (10). This Editorial Focus underscores the conundrum of intricate signaling pathways alluded to in a recent article in the American Journal of Physiology-Renal Physiology by Manickam et al. (13) with the end point being renal fibrosis. In renal fibrosis, there is excessive amassing of the extracellular matrix (ECM) under the influence of profibrogenic cytokines, which initiate a myriad of signaling cascades. Under such stimuli, certain renal mesenchymal cells, such as mesangial cells and fibroblasts, differentiate upon activation into a profibrogenic myofibroblast phenotype and synthesize excessive amounts of the ECM (1, 10). TGF-1, a prototype of the TGF- superfamily, is widely considered to be the major profibrogenic cytokine that is responsible for the myofibroblast differentiation with ECM synthesis along with the suppression of ECM-degrading enzymes (11). TGF-1 first binds to a type II serine/threonine kinase receptor, which transphosphorylates and activates a type I receptor followed by the commencement of a series of downstream signaling events. In the canonical pathway, the activated TGF-1 receptor interacts with