Uterine Sensitization-Associated Gene-1 in the Progression of Kidney Diseases.

Uterine sensitization-associated gene-1 (USAG-1), originally identified as a secretory protein preferentially expressed in the sensitized rat endometrium, has been determined to modulate bone morphogenetic protein (BMP) and Wnt expression to play important roles in kidney disease. USAG-1 affects the progression of acute and chronic kidney damage and the recovery of allograft kidney function by regulating the BMP and Wnt signaling pathways. Moreover, USAG-1 has been found to be involved in the process of T cell immune response, and its ability to inhibit germinal center activity and reduce humoral immunity is of great significance for the treatment of autoimmune nephropathy and antibody-mediated rejection (AMR) after renal transplantation. This article summarizes the many advances made regarding the roles of USAG-1 in the progression of kidney disease and outlines potential treatments.

Structural basis of BMP-2 and BMP-7 interactions with antagonists Gremlin-1 and Noggin in Glioblastoma tumors.

In Glioblastoma (GBM) brain tumors, both Gremlin-1 and Noggin are reported to bind to BMP and inhibit BMP-signaling, thereby allowing the cell to maintain tumorous morphology. Enlisting the interfacial residues important for protein-protein complex formation between BMPs (BMP-2 and BMP-7) and antagonists (Gremlin-1 and Noggin), we analyzed the structural basis of their interactions. We found possible key mutations that destabilize these complexes, which may prevent GBM development. It was also observed that when the interfacial residues were either mutated to histidine or tryptophan, it led to higher destabilization energy values. Besides, our study of the Noggin interactive model of BMP-2 suggested preferential binding at binding site II over binding site I. In the case of Gremlin-1 and BMPs, our research, along with few previous studies, indicates a close-ended cis-trans interactive model.

All-trans retinoic acid can antagonize osteoblastogenesis induced by different BMPs irrespective of their dimerization types and dose-efficiencies.

INTRODUCTION: Alcoholism can lead to low mineral density, compromised regenerative bone capacity and delayed osteointegration of dental implants. This may be partially attributed to the inhibitive effect of all-trans retinoic acid (ATRA), a metabolite of alcohol, on osteoblastogenesis. Our previous studies demonstrated that heterodimeric bone morphogenetic protein 2/7 (BMP2/7) was a more potent BMP than homodimeric BMP2 or BMP7, and could antagonize the inhibitive effect of ATRA to rescue osteoblastogenesis. MATERIALS AND METHODS: In this study, we compared the effectiveness of BMP2/7, BMP2 and BMP7 in restoring osteoblastogenesis of murine preosteoblasts upon inhibition with 1 µM ATRA, and we further analyzed the potential mechanisms. We measured the following parameters: cell viability, ALP, OCN, mineralization, the expression of osteogenic differentiation marker genes (Collagen I, ALP and OCN) and the expression of BMP signaling key genes (Dlx5, Runx2, Osterix and Smad1). RESULTS: BMP2/7 treatment alone induced significantly higher osteoblastogenesis compared to BMP2 and BMP7. When cells were treated by ATRA, BMP2/7 was superior only in rescuing cell viability and ALP activity, compared to BMP2 or BMP7. However, BMP2/7 was not superior to BMP2 or BMP7 in restoring OCN expression and extracellular mineralized nodules, or in rescuing expression of two key osteogenic genes, Dlx5 and Runx2. Irrespective of their dimeric types or potency, the selected BMPs could antagonize the inhibitory effect of ATRA on osteoblastogenesis. CONCLUSION: The presence of ATRA, BMP2/7 still induced significantly higher cell viability and early differentiation than the homodimers. However, ATRA significantly attenuated the advantages of BMP2/7 in inducing late and final osteoblastogenic differentiation over the homodimers.

E4BP4 promotes thyroid cancer proliferation by modulating iron homeostasis through repression of hepcidin.

Iron homeostasis is critical to mammals, and dysregulation in iron homeostasis usually leads to severe disorders including various cancers. Massive hepcidin secretion is an indicator of thyroid cancer, but the molecular mechanisms responsible for this dysregulation are unknown. Hepcidin secretion from thyroid cancer cells also leads to decreased expression of the iron exporter, ferroportin (FPN), and increased intracellular iron retention, which promote cancer proliferation. In this study, we examined the role of hepcidin in thyroid cancer (TC) and the molecular bases of its signaling. Synthesis of hepcidin is regulated by the BMP4/7 agonist SOSTDC1, which was downregulated in TC; SOSTDC1 downregulation was correlated with G9a-mediated hypermethylation in its promoter. The binding of G9a to the SOSTDC1 promoter requires E4BP4, which interacts with G9a to form a multi-molecular complex that contributes to SOSTDC1 silencing. Silencing of E4BP4 or G9a has similar effects to SOSTDC1 overexpression, which suppresses secretion of hepcidin and inhibits TC cell proliferation. Furthermore, our in vivo xenograft data indicated that depletion of E4BP4 also inhibits cancer growth, reduces hepcidin secretion, and reduces G9a nuclear transportation. Iron homeostasis and tumor growth in TC may be regulated by an E4BP4-dependent epigenetic mechanism. These findings suggest a new mechanism of cellular iron dysfunction through the E4BP4/G9a/SOSTDC1/hepcidin pathway, which is an essential link in TC.

Suppression of BMP-7 by histone deacetylase 2 promoted apoptosis of renal tubular epithelial cells in acute kidney injury.

Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by histone deacetylase (HDAC) inhibitors via epigenetic modification to enhance bone morphogenetic protein 7 (BMP-7) expression. Cisplatin upregulated the activity of HDAC2 in the kidney. Inhibition of HDAC with clinically used trichostatin A (TSA) or valproic acid (VPA) suppressed cisplatin-induced kidney injury and epithelial cell apoptosis. Overexpression of HDAC2 promotes CP-treated tubular epithelium cells apoptosis. Chromatin immunoprecipitation assay clearly detected HDAC2 assosiation with BMP-7 promoter. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by TSA or VPA in vivo and in vitro. Interestingly, administration of recombinant BMP-7 (rhBMP-7) reduced cisplatin-induced kidney dysfunction. Moreover, BMP-7 treatment suppressed epithelial cell apoptosis and small interfering RNA-based knockdown of BMP-7 expression abolished HDAC inhibitors suppression of epithelial cell apoptosis in vitro. Results of current study indicated that TSA or VPA inhibited apoptosis of renal tubular epithelial cells via promoting the level of BMP-7 epigenetically through targeting HDAC2. Hence, HDAC inhibitors could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity.

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells.

Colon cancer is common worldwide and accounts for the significant cancer related morbidity and mortality in patients. Although extensive advancement has been made in colon cancer treatment and diagnosis in the last decades, there is still a giant gap between the clinical expectation. It has been reported that resveratrol (Res) may be a potential candidate for cancer treatment. However, the specific mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Res in human colon cancer cells, and unveiled the possible mechanism for this effect. With cell viability, flow cytometry, PCR and western blot analysis, we demonstrated the efficacious anticancer activity of Res in HCT116 cells. Mechanically, we found that Res greatly upregulates BMP7 in HCT116 cells. Exogenous BMP7 enhances the anticancer effect of Res in HCT116 cells, which was almost reversed by the BMP7 specific antibody. Res does not activate the BMPs/Smads signaling, but decreases the phosphorylation of Akt1/2/3 substantially in HCT116 cells. Exogenous BMP7 enhances the inhibitory effect of Res on the phosphorylation of Akt1/2/3, while BMP7 immunodepletion reverses this effect notably. Res markedly decreases the phosphorylation of PTEN, which can be enhanced by exogenous BMP7 but partly reversed by the BMP7 antibody. Our findings suggested that Res may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating BMP7 to decrease, at least, the phosphorylation of PTEN.

MicroRNA-137 inhibits BMP7 to enhance the epithelial-mesenchymal transition of breast cancer cells.

Bone morphogenetic protein-7 (BMP7) is known to antagonize transforming growth factor ß 1 (TGFß1)-mediated fibrosis through suppressing epithelial-mesenchymal transition (EMT). We recently reported that BMP7 also antagonizes the effects of TGFß1 in breast cancer (BC) tumorigenesis-related EMT. Nevertheless, the control of BMP7 expression in BC remains ill-defined. Here, we detected significantly lower levels of BMP7 and significantly higher levels of microRNA-137 (miR-137) in the BC specimens, relative to paired adjacent non-tumor breast tissue. BMP7 and miR-137 levels were correlated inversely. Additionally, the high miR-137 levels in BC specimens were correlated with reduced patient survival. In vitro, overexpression of miR-137 significantly increased cell EMT and invasion, while depletion of miR-137 significantly decreased cell EMT and invasion in BC cells. The increases in BC cell invasiveness by miR-137 appeared to result from its suppression of BMP7, through direct binding of miR-137 to the 3'-UTR of BMP7 mRNA, thereby blocking its protein translation in BC cells. This study sheds light on miR-137 as a crucial factor that enhances BC cell EMT and invasiveness, and points to miR-137 as a promising innovative therapeutic target for BC treatment.

Commercially Available Preparations of Recombinant Wnt3a Contain Non-Wnt Related Activities Which May Activate TGF-ß Signaling.

The Wnt ligands are a family of secreted signaling proteins which play key roles in a number of cellular processes under physiological and pathological conditions. Wnts bind to their membrane receptors and initiate a signaling cascade which leads to the nuclear localization and transcriptional activity of ß-catenin. The development of purified recombinant Wnt ligands has greatly aided in our understanding of Wnt signaling and its functions in development and disease. In the current study, we identified non-Wnt related signaling activities which were present in commercially available preparations of recombinant Wnt3a. Specifically, we found that treatment of cultured fibroblasts with recombinant Wnt3a induced immediate activation of TGF-ß and BMP signaling and this activity appeared to be independent of the Wnt ligand itself. Therefore, while purified recombinant Wnt ligands continue to be a useful tool for studying this signaling pathway, one must exercise a degree of caution when analyzing the results of experiments that utilize purified recombinant Wnt ligands.

Lysine-specific demethylase 5C promotes hepatocellular carcinoma cell invasion through inhibition BMP7 expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of tumor and is associated with high morbidity and mortality rates. Patients with HCC routinely undergo surgery followed by adjuvant radiation therapy and chemotherapy. Despite such aggressive treatment approaches, median survival times remain under 1 year in most cases. KDM5C is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). KDM5C has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in HCC remain unclear. METHODS: Expression level of KDM5C was examined by RT-PCR, and IHC. Forced expression of KDM5C was mediated by retroviruses, and KDM5C was downregulated by shRNAs expressing lentiviruses. Migration and invasion of HCC cells was measured by wound healing, Transwell and Matrigel assays respectively. RESULTS: In this study, we report that KDM5C is abundantly expressed in invasive human HCC cells. Cellular depletion of KDM5C by shRNA inhibited HCC cell migration, invasion and epithelial-mesenchymal transition in vitro, and markedly decreased the metastasis capacity of invasive HCC cells in the liver and lung. Furthermore, ectopic expression of KDM5C in HCC cells promoted cell migration, invasion and epithelial-mesenchymal transition via the inactivation of BMP7. Knockdown of BMP7 significantly promotes shKDM5C-induced cell migration inhibition. CONCLUSIONS: Taken together, these data suggest that KDM5C-mediated BMP7 inactivation is essential for HCC cell invasion.

Angiopoietin-like 4 enhances metastasis and inhibits apoptosis via inducing bone morphogenetic protein 7 in colorectal cancer cells.

Angiopoietin-like 4 (ANGPTL4), a secretory glycoprotein, plays an important role in cancer metastasis. In the present study, we aim to investigate the roles and mechanisms of ANGPTL4 in the regulation of colorectal cancer metastasis. We found that expression level of ANGPTL4 was increased in colorectal cancer tissues, compared with that in normal tissues. Moreover, liver metastasis was significantly associated with higher expression of ANGPTL4. In vitro studies further showed that overexpression of ANGPTL4 enhanced cell migration, invasion and inhibited apoptosis. At the molecular level, ANGPTL4 overexpression resulted in an up-regulation of bone morphogenetic protein 7 (BMP7). Indeed, knockdown of BMP7 by small interfering RNA (siRNA) oligos reversed the roles of ANGPTL4 overexpression in HCT116 cells. Finally, in vivo studies further confirmed the metastatic roles of ANGPTL4 by inducing BMP7. Therefore, our study demonstrated that ANGPTL4 might promote metastasis and might inhibit apoptosis of colorectal cancer cells by up-regulation of BMP7.

Structure of neuroblastoma suppressor of tumorigenicity 1 (NBL1): insights for the functional variability across bone morphogenetic protein (BMP) antagonists.

Bone morphogenetic proteins (BMPs) are antagonized through the action of numerous extracellular protein antagonists, including members from the differential screening-selected gene aberrative in neuroblastoma (DAN) family. In vivo, misregulation of the balance between BMP signaling and DAN inhibition can lead to numerous disease states, including cancer, kidney nephropathy, and pulmonary arterial hypertension. Despite this importance, very little information is available describing how DAN family proteins effectively inhibit BMP ligands. Furthermore, our understanding for how differences in individual DAN family members arise, including affinity and specificity, remains underdeveloped. Here, we present the structure of the founding member of the DAN family, neuroblastoma suppressor of tumorigenicity 1 (NBL1). Comparing NBL1 to the structure of protein related to Dan and Cerberus (PRDC), a more potent BMP antagonist within the DAN family, a number of differences were identified. Through a mutagenesis-based approach, we were able to correlate the BMP binding epitope in NBL1 with that in PRDC, where introduction of specific PRDC amino acids in NBL1 (A58F and S67Y) correlated with a gain-of-function inhibition toward BMP2 and BMP7, but not GDF5. Although NBL1(S67Y) was able to antagonize BMP7 as effectively as PRDC, NBL1(S67Y) was still 32-fold weaker than PRDC against BMP2. Taken together, this data suggests that alterations in the BMP binding epitope can partially account for differences in the potency of BMP inhibition within the DAN family.

Mesenchymal stem cells mitigate cirrhosis through BMP7.

BACKGROUND/AIMS: Transplantation of mesenchymal stem cells (MSCs) has therapeutic effects on various diseases, while its effect on developing cirrhosis as well as the underlying mechanism remained largely unknown. METHODS: Twenty C57BL/6 mice were randomly separated into 2 groups of ten each. One group received transplantation of MSCs, while the other group received saline as control. The mice then received intraperitoneal injection of carbon tetrachloride (CCl4) twice per week for 8 weeks to develop cirrhosis. After another 4 weeks, the levels of cirrhosis in these mice were evaluated by liver fibrosis area, portal pressure, sodium balance and excretion. Transcripts of transforming growth factor ß 1 (TGFß1) and bone morphogenic protein 7 (BMP7) in the mouse livers were quantified by RT-qPCR. BMP7-depleted MSCs were prepared and applied in this model, and compared to MSCs. RESULTS: Liver fibrosis, portal hypertension and sodium retention that were developed by CCl4, were all significantly alleviated by MSCs transplantation, which decreased TGFß1 levels and increased BMP7 levels in the injured liver. MSCs were found to express extremely high levels of BMP7. Knockdown of BMP7 in MSCs completely abolished the protective effect of MSCs against CCl4-induced cirrhosis. CONCLUSIONS: MSCs mitigate cirrhosis through their production of BMP7 against the fibrogenic effect of TGFß1 in the injured liver.

Dynamics of BMP signaling in limb bud mesenchyme and polydactyly.

Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis.

Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations.

Bone morphogenetic proteins (BMPs) are highly conserved signaling molecules that are part of the transforming growth factor (TGF)-beta superfamily, and function in the patterning and morphogenesis of many organs including development of the dentition. The functions of the BMPs are controlled by certain classes of molecules that are recognized as BMP antagonists that inhibit BMP binding to their cognate receptors. In this study we tested the hypothesis that USAG-1 (uterine sensitization-associated gene-1) suppresses deciduous incisors by inhibition of BMP-7 function. We learned that USAG-1 and BMP-7 were expressed within odontogenic epithelium as well as mesenchyme during the late bud and early cap stages of tooth development. USAG-1 is a BMP antagonist, and also modulates Wnt signaling. USAG-1 abrogation rescued apoptotic elimination of odontogenic mesenchymal cells. BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced. Using explant culture and subsequent subrenal capsule transplantation of E15 USAG-1 mutant maxillary incisor tooth primordia supplemented with BMP-7 demonstrated in USAG-1+/- as well as USAG-1-/- rescue and supernumerary tooth development. Based upon these results, we conclude that USAG-1 functions as an antagonist of BMP-7 in this model system. These results further suggest that the phenotypes of USAG-1 and BMP-7 mutant mice reported provide opportunities for regenerative medicine and dentistry.

Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

HDAC dependent transcriptional repression of Bmp-7 potentiates TGF-ß mediated renal fibrosis in obstructive uropathy.

PURPOSE: Recombinant BMP-7 inhibits the pathogenesis of renal injury in response to various stimuli. However, little is known about the molecular regulation of endogenous BMP-7 and its renal protective functions. We examined transcriptional regulation of Bmp-7 and its role in the pathogenesis of renal injury resulting from urinary tract dysfunction. MATERIALS AND METHODS: Obstruction induced renal injury was modeled in vivo in mice by unilateral ureteral obstruction and in vitro in primary kidney cells by treatment with transforming growth factor-ß, a profibrotic cytokine that is increased in the obstructed kidney. RESULTS: Unilateral ureteral obstruction resulted in the loss of BMP-7 expression in conjunction with histone deacetylation and transcriptional repression of the Bmp-7 promoter. The histone deacetylase inhibitor trichostatin A stimulated Bmp-7 expression in primary kidney cells. Trichostatin A also inhibited the expression of transforming growth factor-ß dependent profibrotic genes in a manner that depended on BMP receptor signaling. These findings extended to the obstructed kidney in vivo, in which trichostatin A treatment restored the expression of Bmp-7 along with BMP-7 mediated suppression of transforming growth factor-ß dependent signaling pathways. Finally, trichostatin A stimulated activation of the BMP-7 pathway the ameliorated obstruction induced renal injury by preventing disruption of the renal architecture and the development of renal fibrosis. CONCLUSIONS: These findings show that histone deacetylase dependent repression of Bmp-7 transcription is a critical event during the pathogenesis of renal injury in obstructive uropathy. Accordingly, treatment with histone deacetylase inhibitors represents a potentially effective strategy to restore BMP-7 expression and its renal protective functions during treatment of obstructive uropathy.

FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney.

Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1(-/-) tissue. We found that although nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we screened for target genes by comparison of Foxd1 null and wild-type tissues. We found that the gene encoding the small leucine-rich proteoglycan decorin (DCN) is repressed by FOXD1 in cortical interstitial cells, and we show that compound genetic inactivation of Dcn partially rescues the failure of progenitor cell differentiation in the Foxd1 null. We demonstrate that DCN antagonizes BMP/SMAD signaling, which is required for the transition of CITED1-expressing nephron progenitor cells to a state that is primed for WNT-induced epithelial differentiation. On the basis of these studies, we propose a mechanism for progenitor cell retention in the Foxd1 null in which misexpressed DCN produced by prematurely differentiated interstitial cells accumulates in the extracellular matrix, inhibiting BMP7-mediated transition of nephron progenitor cells to a compartment in which they can respond to epithelial induction signals.

EGF stimulates Müller glial proliferation via a BMP-dependent mechanism.

Müller glia, the major type of glia in the retina, are mitotically quiescent under normal conditions, though they can be stimulated to proliferate in some pathological states. Among these stimuli, EGF is known to be a potent mitogen for Müller glia. However, the signaling pathways required for EGF-mediated proliferation of Müller glia are not clearly understood. In this study, postnatal day 12 (P12) or adult trp53(-/-) mouse retinas were explanted and cultured in the presence of EGF to stimulate Müller glial proliferation. Treatment with signaling inhibitors showed that activation of both MEK/ERK1/2 and PI3K/AKT pathways is required for EGF-induced proliferation of Müller glia. Interestingly, BMP/Smad1/5/8 activation downstream of PI3K/AKT signaling was also necessary for robust Müller glial proliferation, though activation of BMP/Smad1/5/8 signaling alone failed to stimulate their proliferation. In dissociated Müller glial culture, treatment with EGF induced the upregulation of Bmp7, and this upregulation was blocked significantly by co-treatment with the BMP inhibitor dorsomorphin, suggesting that BMP/Smad1/5/8 activation is mediated at least in part by an autocrine mechanism in Müller glia. A better understanding of how BMP/Smad1/5/8 signaling is involved in glial proliferation may have important implications for proliferative disorders, as well as for retinal regeneration in mammalian retinas.

Role of the TGF-ß/BMP-7/Smad pathways in renal diseases.

TGF-ß (transforming growth factor-ß) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-ß superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-ß and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-ß signalling is up-regulated by inducing TGF-ß1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-ß1 induces Smurf2, a ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-ß/Smad signalling and has therapeutic effect on CKDs. Recent studies also found that Smad3 mediated renal fibrosis by up-regulating miR-21 (where miR represents microRNA) and miR-192, but down-regulating miR-29 and miR-200 families. Therefore restoring miR-29/miR-200 or suppressing miR-21/miR-192 is able to treat progressive renal fibrosis. Furthermore, activation of TGF-ß/Smad signalling inhibits renal BMP-7 expression and BMP/Smad signalling. On the other hand, overexpression of renal BMP-7 is capable of inhibiting TGF-ß/Smad3 signalling and protects the kidney from TGF-ß-mediated renal injury. This counter-regulation not only expands our understanding of the causes of renal injury, but also suggests the therapeutic potential by targeting TGF-ß/Smad signalling or restoring BMP-7 in CKDs. Taken together, the current understanding of the distinct roles and mechanisms of TGF-ß and BMP-7 in CKDs implies that targeting the TGF-ß/Smad pathway or restoring BMP-7 signalling may represent novel and effective therapies for CKDs.

Inhibitors/antagonists of TGF-ß system in kidney fibrosis.

Renal fibrosis is a major hallmark of chronic kidney disease, regardless of the initial causes, and prominent renal fibrosis predicts poor prognosis for renal insufficiency. Transforming growth factor (TGF)-ß plays a pivotal role in the progression of renal fibrosis, and therapeutic interventions targeting TGF-ß have been successful and well tolerated in animal models. However, these interventions might have adverse effects by inducing systemic inflammation due to the strong bifunctional role of TGF-ß (pro-fibrotic and anti-inflammatory). This review of the current literature focuses on the inhibitors/antagonists of TGF-ß, and discusses possible therapeutic approaches targeting them, describing the effectiveness of orally active bone morphogenetic protein 7 mimetics in reversing established fibrosis. It will conclude with a brief discussion of possible future directions for research.