BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury

Abstract

Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.

Sorafenib inhibits transforming growth factor β1-Mediated Epithelial-Mesenchymal Transition and apoptosis in mouse hepatocytes

“…Given the prominent role of TGFb in EMT and fibrogenesis, a number of strategies for blocking TGF-b signaling have been proposed. [22][23][24] Small molecules targeting this signaling cascade have great therapeutic potential. To identify such candidates, a drug library screen was performed using (CAGA) 12 -Lux, a luciferase reporter that is activated in response to a wide range of TGF-b1 concentrations (Supporting Fig.…”

“…Several gene therapy approaches using dominant-negative TGF-b receptors and BMP-7 have been developed to prevent fibrosis in different tissues. 22,23 Similarly, ectopic overexpression of Smad7 in the hepatocytes of transgenic mice was shown to attenuate TGF-b signaling and thereby improve CCl 4 -induced liver fibrosis. 24 In addition to these protein-based therapies, small molecules and biological agents that act on this signaling cascade have shown strong therapeutic potential in clinical settings.…”

Fibrocytes are involved in the pathogenesis of human chronic kidney disease

“…Especially, the severity of interstitial fibrosis has been reported to determine the prognosis of kidney function [2]. To date, resident fibroblasts, epithelial-mesenchymal transition (EMT)-derived fibroblasts/myofibroblasts, and monocytes/macrophages have been suggested to be involved in the progression of kidney diseases [3,4]. However, the precise pathogenic mechanisms of tubulointerstitial lesions, especially related to interstitial fibrosis, in patients with CKD remain to be determined.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…120 BMP7 is a member of the TGF-b superfamily. [121][122][123] BMP7 binds to three type I receptors, activin-like kinases (Alk) -2, -3 and -6, and a Figure 1 Working hypothesis of combating aging kidney. The kidney continuously suffers from various physiological/pathological stresses/toxins, and several such factors could accelerate kidney aging.…”