Abstract
The basic-Helix-Loop-Helix family (bHLH) of transcriptional factors plays a major role in regulating cellular proliferation, differentiation and phenotype maintenance. The downregulation of one of the members of bHLH family protein, inhibitor of DNA binding 2 (Id2) has been shown to induce de-differentiation of epithelial cells. Opposing regulators of epithelial/mesenchymal phenotype in renal proximal tubule epithelial cells (PTEC), TGFβ1 and BMP7 also have counter-regulatory effects in models of renal fibrosis. We investigated the regulation of Id2 by these growth factors in human PTECs and its implication in the expression of markers of epithelial versus myofibroblastic phenotype. Cellular Id2 levels were reduced by TGFβ1 treatment; this was prevented by co-incubation with BMP7. BMP7 alone increased cellular levels of Id2. TGFβ1 and BMP7 regulated Id2 through Smad2/3 and Smad1/5 dependent mechanisms respectively. TGFβ1 mediated Id2 suppression was essential for α-SMA induction in PTECs. Although Id2 over-expression prevented α-SMA induction, it did not prevent E-cadherin loss under the influence of TGFβ1. This suggests that the loss of gate keeper function of E-cadherin alone may not necessarily result in complete EMT and further transcriptional re-programming is essential to attain mesenchymal phenotype. Although BMP7 abolished TGFβ1 mediated α-SMA expression by restoring Id2 levels, the loss of Id2 was not sufficient to induce α-SMA expression even in the context of reduced E-cadherin expression. Hence, a reduction in Id2 is critical for TGFβ1-induced α-SMA expression in this model of human PTECs but is not sufficient in it self to induce α-SMA even in the context of reduced E-cadherin.
Highlights
The inhibitor of DNA binding 2 (Id2) protein belongs to the basic-Helix-Loop-Helix family of transcriptional regulators which are involved in cell cycle entry and proliferation [1], survival [2], differentiation and lineage commitment [3,4]
Though published reports support the role of Id2 in the regulation of Ecadherin and a-SMA, it has not been studied in the context of TGFb1 and BMP 7 in human renal proximal tubule epithelial cells (PTEC). Since these growth factors play a pivotal role in the regulation of renal fibrosis by regulating PTEC phenotype, we investigated the regulation of Id2 by these two growth factors in relation to the expression of key markers of epithelial phenotype to a mesenchymal phenotype (EMT)
In particular we investigated whether counterregulation of Id2 by BMP 7 may account for its anti-fibrotic effect by inhibiting TGFb1 mediated expression of a-SMA and the myofibroblastic transition of PTECs
Summary
The inhibitor of DNA binding 2 (Id2) protein belongs to the basic-Helix-Loop-Helix (bHLH) family of transcriptional regulators which are involved in cell cycle entry and proliferation [1], survival [2], differentiation and lineage commitment [3,4]. Phenotypic transition of differentiated epithelial cells has been studied extensively in the context of pathological tissue fibrosis. It has been disputed [7], the transition of epithelial phenotype to a mesenchymal phenotype (EMT) is considered as one of the sources of matrix secreting fibroblasts in fibrosis involving vital organs like kidney, liver and lung [8,9,10]. A growing body of evidence from both in vitro and animal studies confirm the occurrence of EMT in renal epithelial cells [12,13,14], the reports from human samples are sparse [8,15]
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