12/22/2023 0 Comments Michael haak redditProposed signaling processes include pathways arising from TGF- β1, Wnt, BMP, and/or Notch. 5–8 The pathways activating myofibroblasts are also unsettled multiple signaling pathways have been proposed to be activators of myofibroblasts. 4 A key step in the development of tissue fibrosis is sustained activation of myofibroblasts, but the source of these cells is controversial: suggested origins include the bone marrow, activated interstitial fibroblasts, or fibroblasts that result from Epithelial-Mesenchymal Transition or from Endothelial-Mesenchymal Transition. 3 Although these changes have been considered to be a protective response to maintain tissue integrity, the presence of fibrosis markedly depresses the regenerative potential of the kidney and leads to a decline in kidney function. 1, 2 Hallmarks of interstitial fibrosis in the kidney include proliferation of myofibroblasts and excessive deposition of extracellular matrix (ECM). The development of interstitial fibrosis in the kidney is linked to progressive kidney damage and CKD. Identifying mechanisms that interrupt this profibrotic cycle could lead to the development of anti-fibrosis therapy. Thus, in the kidney, Yap is a tissue mechanosensor that can be activated by ECM and transforms fibroblasts into myofibroblasts the interaction of Yap/Taz and ECM forms a feed-forward loop resulting in kidney fibrosis. In a UUO-release model, induction of Gli1 + cell-specific Yap/Taz knockout partially reversed the development of interstitial fibrosis. Furthermore, Gli1 + cell-specific knockout of Yap/Taz in mice suppressed UUO-induced ECM deposition, myofibroblast accumulation, and interstitial fibrosis. In mice with UUO, the Yap inhibitor verteporfin reduced interstitial fibrosis. Moreover, in the absence of TGF- β1, fibroblasts seeded on a stiffened ECM transformed into myofibroblasts in a process dependent on the activation of Yap. In cultured fibroblasts, inhibition of Yap/Taz signaling blocked TGF- β1–induced fibroblast-to-myofibroblast transformation and ECM production, whereas constitutive activation of Yap promoted fibroblast transformation and ECM production even in the absence of TGF- β1. ![]() In mice, Yap expression increased in renal fibroblasts after unilateral ureteral obstruction (UUO), in association with worsening of interstitial fibrosis. We hypothesized that the development of kidney fibrosis depends on Yap-induced activation and proliferation of kidney fibroblasts. The transcriptional coactivators yes-associated protein ( Yap) and transcriptional coactivator with PDZ-binding motif (Taz) function as mechanosensors in cancer cells and have been implicated in the regulation of myofibroblasts in the kidney. ![]() In damaged kidneys, increased extracellular matrix (ECM) and tissue stiffness stimulate kidney fibrosis through incompletely characterized molecular mechanisms.
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