Trps1 Haploinsufficiency Promotes Renal Fibrosis by Increasing Arkadia Expression

Autor: Shunji Itoh, Ting Gui, Zhibo Gai, Kosuke Oikawa, Yasuteru Muragaki, Gengyin Zhou, Kohsaku Uetani
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Popis: Chronic kidney disease is irreversible, but progressive renal fibrosis is commonly observed regardless of the cause of the diseases. One of the main effector cells that contribute to the development of progressive renal fibrosis is the tubulointerstitial fibroblast. Importantly, in tubulointerstitial fibrosis, a large proportion of the interstitial fibroblasts originate from tubular epithelial cells via an epithelial-to-mesenchymal transition (EMT).1,2 During the process of EMT, tubular epithelial cells lose their epithelial phenotype and acquire a mesenchymal phenotype, which includes disruption of polarized tubular epithelial cell morphology, de novo α-smooth muscle actin (α-SMA) expression and actin reorganization, loss of cell-cell adhesions through downregulation of E-cadherin, destruction of the basement membrane, and increased cell migration and invasion.3,4 Consequently, this process induces renal tubular destruction and accumulation of myofibroblasts. TGF-β1 is proposed to be the major regulator of EMT induction.5 In recent years, the receptors and signal transduction pathways mediating the effects of TGF-β in cells have been identified, and Smad proteins are critical intracellular mediators in the TGF-β signaling pathway.6–9 The transduction of TGF-β/Smad signaling occurs as follows: upon TGF-β binding to TβRII, TβRI is phosphorylated by TβRII, and the activated TβRI associates transiently with R-Smads (Smad2 and Smad3) and phosphorylates them. The phosphorylated R-Smads dissociate from the receptor, bind to Smad4, and translocate into the nucleus, where this Smad complex controls the transcription of TGF-β-responsive genes together with additional DNA-binding cofactors. In contrast to R-Smads, Smad7 attenuates TGF-β signaling through multiple mechanisms, including interaction with activated TβRI and inhibition of R-Smad phosphorylation.10,11 These observations suggest that the ability of TGF-β to induce EMT depends on the balance between positive and negative Smad signals. Cellular protein levels are modulated dynamically by the ubiquitin-proteasome degradation pathway.12,13 Smad protein levels are regulated by ubiquitin-mediated proteolysis. E3 ubiquitin ligases, such as Arkadia and Smad ubiquitination regulatory factors (Smurfs), are involved in the proteasomal degradation of Smad7.9,14 Smad7 has been shown to function as an adaptor protein that recruits Smurf ubiquitin ligases to the TGF-β receptor complex to promote the degradation of the complex.15,16 In contrast with Smurfs, Arkadia regulates the transcriptional activity of TGF-β only through degradation of Smad7 and not through that of TGF-β receptors.14 In our previous studies, we demonstrated that Trps1 functions downstream of Bmp7 and is required for the mesenchymal-to-epithelial transition and for regulation of ureteric bud branching in the embryonic kidney.17 However, the role of Trps1 in the adult kidney is still unknown. In this study, we examined Trps1 expression in adult mouse kidneys and found that it was restricted to proximal tubular epithelial cells in the cortex region. Moreover, we used a unilateral ureteral obstruction (UUO) model of renal fibrosis and examined primary proximal tubular epithelial cells from wild-type and heterozygous Trps1-null mice. We demonstrate that heterozygous loss of Trps1 promotes renal fibrosis by activating the TGF-β/Smad3 signaling pathway.
Databáze: OpenAIRE
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