Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells

Emerging evidence suggests that tubular epithelial-myofibroblast transdifferentiation is an important event in renal tubulointerstitial fibrosis. This review describes the recent findings in the context of the tubular epithelial-myofibroblast transdifferentiation process and discusses the possible mechanisms involved.

Tubular epithelial-myofibroblast transdifferentiation is a complex process involving disruption of polarized tubular epithelial cell morphology into cells with spindle-shaped mesenchymal morphology, formation of actin stress fibers, loss of cell-cell adhesions through downregulation of E-cadherin, destruction of basement membrane, and increased cell migration and invasion. This phenotypic transition has also been recently reported in human glomerulonephritis with progressive tubulointerstitial fibrosis. Transforming growth factor-beta is a key fibrogenic growth factor that regulates tubular epithelial-myofibroblast transdifferentiation, which is counter-regulated by hepatocyte growth factor. In addition, basic fibroblast growth factor, advanced glycation end products, and angiotensin II have also been reported to induce the process. Importantly, the recent discovery of transforming growth factor-beta/Smad signaling has allowed the delineation of the intracellular mechanisms of tubular epithelial-myofibroblast transdifferentiation. Indeed, Smad signaling is a key pathway whereby transforming growth factor-beta and angiotensin II induce tubular epithelial-myofibroblast transdifferentiation in vitro. This involves the activation of transforming growth factor-beta receptor-associated Smad2 and is inhibited by an inhibitory Smad protein, Smad7. Thus, Smad signaling plays a critical role in tubular epithelial-myofibroblast transdifferentiation.

Renal myofibroblasts may be derived from tubular epithelial cells by a process of tubular epithelial-myofibroblast transdifferentiation. Transforming growth factor-beta signals through Smads to positively or negatively regulate this process. Blockade of this process by either hepatocyte growth factor or targeting the Smad signaling pathway may provide novel therapeutic strategies to combat renal fibrosis.