Role of the TGF-β/BMP-7/Smad pathways in renal diseases (original) (raw)
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TGF-β/Smad signaling in renal fibrosis
Frontiers in Physiology, 2015
TGF-β (transforming growth factor-β) is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF-β signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix), and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases (CKD). Taken together, TGF-β/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for CKD associated with renal fibrosis.
Transforming growth factor-beta and Smad signalling in kidney diseases. Review Article
Nephrology, 2005
Extensive studies have demonstrated that transforming growth factor-beta (TGFb) plays an important role in the progression of renal diseases. TGFb exerts its biological functions mainly through its downstream signalling molecules, Smad2 and Smad3. It is now clear that Smad3 is critical for TGFb 's pro-fibrotic effect, whereas the functions of Smad2 in fibrosis in response to TGFb still need to be determined. Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE). These pro-fibrotic factors can activate Smads directly and independently of TGFb. They can also cause renal fibrosis via the ERK/p38 MAP kinase-Smad signalling cross-talk pathway. In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGFb , angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases. Results from these studies indicate that Smad signalling is a key and final common pathway of renal fibrosis. In addition, TGFb has anti-inflammatory and immuneregulatory properties. Our most recent studies demonstrated that TGFb transgenic mice are protected against renal inflammation in mouse obstructive and diabetic models. Upregulation of renal Smad7, thereby blocking NF. k B activation via induction of I k B a , is a central mechanism by which TGFb inhibits renal inflammation. In conclusion, TGFb signals through Smad2/3 to mediate renal fibrosis, whereas induction of Smad7 inhibits renal fibrosis and inflammation. Thus, targeting Smad signalling by overexpression of Smad7 may have great therapeutic potential for kidney diseases.
Diverse roles of TGF-β/Smads in renal fibrosis and inflammation
International journal of biological sciences, 2011
TGF-β1 has been long considered as a key mediator in renal fibrosis and induces renal scarring largely by activating its downstream Smad signaling pathway. Interestingly, while mice overexpressing active TGF-β1 develop progressive renal injury, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Under disease conditions, Smad2 and Smad3 are highly activated, while Smad7 is degraded through the ubiquitin proteasome degradation mechanism. In addition to TGF-β1, many pathogenic mediators such as angiotensin II and advanced glycation end products can also activate the Smad pathway via both TGF-β-dependent and independent mechanisms. Smads interact with other signaling pathways, such as the MAPK and NF-κB pathways, to positively or negatively regulate renal inflammation and fibrosis. Studies from gene knockout mice demonstrate that TGF-β1 acts by stimulating its downstream Smads to diversely regulate kidney injury. In the context of renal fibrosis and inflammation, ...
The preventive and therapeutic implication for renal fibrosis by targeting TGF-β/Smad3 signaling
Clinical science (London, England : 1979), 2018
It is well established that Smad3 is a key downstream effector of TGF-β signaling in tissue fibrogenesis. We report here that targeting Smad3 specifically with a Smad3 inhibitor SIS3 is able to prevent or halt the progression of renal fibrosis in a mouse model of unilateral ureteral obstructive nephropathy (UUO). We found that preventive treatment with SIS3 at the time of disease induction largely suppressed progressive renal fibrosis by inhibiting a-SMA+ myofibroblast accumulation and extracellular matrix (collagen I and fibronectin) production. Importantly, we also found that treatment with SIS3 on established mouse model of UUO from day 4 after UUO nephropathy halted the progression of renal fibrosis. Mechanistically, the preventive and therapeutic effect of SIS3 on renal fibrosis was associated with the inactivation of Smad3 signaling and inhibition of TGF-b1 expression in the UUO kidney. In conclusion, results from this study suggest that targeting Smad3 may be a specific and e...
Molecular Mechanisms of TGF-β Signaling in Renal Fibrosis
Current Pathobiology Reports, 2013
Renal fibrosis is the hallmark of various chronic kidney diseases (CKD). Transforming growth factor beta (TGF-b) is recognized as a vital mediator in renal fibrosis as it induces production of extracellular matrix to cause renal scarring. The precise roles of individual Smads, receptors, and co-repressors have been recently characterized, and the results reveal the complexity of TGF-b signaling during CKD. Smad2 and Smad7 play protective roles; however, Smad3 plays a pathogenic role in CKD. Smad4 enhances Smad3-mediated renal fibrosis. Heat-shock protein also plays an essential role in TGF-b/Smad-mediated renal fibrosis. Recent findings demonstrate that microRNAs are critical downstream effectors of TGF-b/Smad3 signaling in renal fibrosis. Thus, targeting the downstream TGF-b/Smad3 signaling pathway by gene transfer of either Smad7-or Smad3-dependent microRNAs, and by applying Smad3 inhibitor and Smad7 agonist may offer a specific and effective therapeutic strategy for renal fibrosis in CKD.
Diverse Role of TGF-β in Kidney Disease
Frontiers in Cell and Developmental Biology
Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Transforming growth factor-β (TGF-β) has been long considered as a key mediator of renal fibrosis. In addition, TGF-β also acts as a potent anti-inflammatory cytokine that negatively regulates renal inflammation. Thus, blockade of TGF-β inhibits renal fibrosis while promoting inflammation, revealing a diverse role for TGF-β in CKD. It is now well documented that TGF-β1 activates its downstream signaling molecules such as Smad3 and Smad3-dependent non-coding RNAs to transcriptionally and differentially regulate renal inflammation and fibrosis, which is negatively regulated by Smad7. Therefore, treatments by rebalancing Smad3/Smad7 signaling or by specifically targeting Smad3dependent non-coding RNAs that regulate renal fibrosis or inflammation could be a better therapeutic approach. In this review, the paradoxical functions and underlying mechanisms by which TGF-β1 regulates in renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGFβ/Smad signaling and transcriptomes are highlighted.
Kidney International, 2012
The mechanism by which TGF-b regulates renal inflammation and fibrosis is largely unclear; however, it is well accepted that its biological effects are mediated through Smad2 and Smad3 phosphorylation. Following activation, these Smads form heteromeric complex with Smad4 and translocate into the nucleus to bind and regulate the expression of target genes. Here we studied the roles of Smad4 to regulate TGF-b signaling in a mouse model of unilateral ureteral obstruction using conditional Smad4 knockout mice and in isolated Smad4 mutant macrophages and fibroblasts. Disruption of Smad4 significantly enhanced renal inflammation as evidenced by a greater CD45 þ leukocyte and F4/80 þ macrophage infiltration and upregulation of IL-1b, TNF-a, MCP-1, and ICAM-1 in the obstructed kidney and in IL-1bstimulated macrophages. In contrast, deletion of Smad4 inhibited renal fibrosis and TGF-b1-induced collagen I expression by fibroblasts. Further studies showed that the loss of Smad4 repressed Smad7 transcription, leading to a loss of functional protein. This, in turn, inhibited IjBa expression but enhanced NF-jB activation, thereby promoting renal inflammation. Interestingly, deletion of Smad4 influenced Smad3-mediated promoter activities and the binding of Smad3 to the COL1A2 promoter, but not Smad3 phosphorylation and nuclear translocation, thereby inhibiting the fibrotic response. Thus, Smad4 may be a key regulator for the diverse roles of TGF-b1 in inflammation and fibrogenesis by interacting with Smad7 and Smad3 to influence their transcriptional activities in renal inflammation and fibrosis.
2010
The mechanism by which TGF-b regulates renal inflammation and fibrosis is largely unclear; however, it is well accepted that its biological effects are mediated through Smad2 and Smad3 phosphorylation. Following activation, these Smads form heteromeric complex with Smad4 and translocate into the nucleus to bind and regulate the expression of target genes. Here we studied the roles of Smad4 to regulate TGF-b signaling in a mouse model of unilateral ureteral obstruction using conditional Smad4 knockout mice and in isolated Smad4 mutant macrophages and fibroblasts. Disruption of Smad4 significantly enhanced renal inflammation as evidenced by a greater CD45þ leukocyte and F4/80þ macrophage infiltration and upregulation of IL-1b, TNF-a, MCP-1, and ICAM-1 in the obstructed kidney and in IL-1bstimulated macrophages. In contrast, deletion of Smad4 inhibited renal fibrosis and TGF-b1-induced collagen I expression by fibroblasts. Further studies showed that the loss of Smad4 repressed Smad7 t...
Smad2 Protects against TGF- /Smad3-Mediated Renal Fibrosis
Journal of the American Society of Nephrology, 2010
Smad2 and Smad3 interact and mediate TGF- signaling. Although Smad3 promotes fibrosis, the role of Smad2 in fibrogenesis is largely unknown. In this study, conditional deletion of Smad2 from the kidney tubular epithelial cells markedly enhanced fibrosis in response to unilateral ureteral obstruction. In vitro, Smad2 knockdown in tubular epithelial cells increased expression of collagen I, collagen III, and TIMP-1 and decreased expression of the matrix-degrading enzyme MMP-2 in response to TGF-1 compared with similarly treated wild-type cells. We obtained similar results in Smad2-knockout fibroblasts. Mechanistically, Smad2 deletion promoted fibrosis through enhanced TGF-/Smad3 signaling, evidenced by greater Smad3 phosphorylation, nuclear translocation, promoter activity, and binding of Smad3 to a collagen promoter (COL1A2). Moreover, deletion of Smad2 increased autoinduction of TGF-1. Conversely, overexpression of Smad2 attenuated TGF-1-induced Smad3 phosphorylation and collagen I matrix expression in tubular epithelial cells. In conclusion, in contrast to Smad3, Smad2 protects against TGF--mediated fibrosis by counteracting TGF-/Smad3 signaling.