Role of bone morphogenetic protein-7 in renal fibrosis

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.

Renal fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease. The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. In a simplistic view, renal fibrosis represents a failed wound-healing process of the kidney tissue after chronic, sustained injury. Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial-mesenchymal transition, have been identified as the major avenues for the generation of the matrix-producing cells in diseased conditions. Among the many fibrogenic factors that regulate renal fibrotic process, transforming growth factor-beta (TGF-beta) is one that plays a central role. Although defective matrix degradation may contribute to tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes in the injured kidney have become increasingly complicated. Recent discoveries on endogenous antifibrotic factors have evolved novel strategies aimed at antagonizing the fibrogenic action of TGF-beta/Smad signaling. Many therapeutic interventions appear effective in animal models; however, translation of these promising results into humans in the clinical setting remains a daunting task. This mini-review attempts to highlight the recent progress in our understanding of the cellular and molecular pathways leading to renal fibrosis, and discusses the challenges and opportunities in developing therapeutic strategies.

Many types of kidney injury induce inflammation as a protective response. However, unresolved inflammation promotes progressive renal fibrosis, which can culminate in end-stage renal disease. Kidney inflammation involves cells of the immune system as well as activation of intrinsic renal cells, with the consequent production and release of profibrotic cytokines and growth factors that drive the fibrotic process. In glomerular diseases, the development of glomerular inflammation precedes interstitial fibrosis; although the mechanisms linking these events are poorly understood, an important role for tubular epithelial cells in mediating this link is gaining support. Data have implicated macrophages in promoting both glomerular and interstitial fibrosis, whereas limited evidence suggests that CD4(+) T cells and mast cells are involved in interstitial fibrosis. However, macrophages can also promote renal repair when the cause of renal injury can be resolved, highlighting their plasticity. Understanding the mechanisms by which inflammation drives renal fibrosis is necessary to facilitate the development of therapeutics to halt the progression of chronic kidney disease.