Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice

Chung, Arthur C.K.; Huang, Xiao Ru; Zhou, Li; Heuchel, Rainer; Lai, Kar Neng; Lan, Hui‐Yao

doi:10.1093/ndt/gfn699

Cited by 168 publications

(204 citation statements)

References 35 publications

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“…Smad7 is one type of inhibitory Smad protein that negatively regulates activation and phosphorylation of Smad2/3. Overexpression of Smad7 could block activation of TGF‐β/Smad signalling while reduction of renal Smad7 could result in over‐activation of TGF‐β/Smad signalling and progression of renal fibrosis 37. In this study, we found AKBA increased the expression of Smad7 in vivo and in vitro experiments.…”

Section: Discussionmentioning

confidence: 51%

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Liu

Shang

et al. 2018

J Cellular Molecular Medi

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Acetyl‐11‐keto‐β‐boswellic acid (AKBA), an active triterpenoid compound from the extract of Boswellia serrate, has been reported previously in our group to alleviate fibrosis in vascular remodelling. This study aimed to elucidate the in vivo and in vitro efficacy and mechanism of AKBA in renal interstitial fibrosis. The experimental renal fibrosis was produced in C57BL/6 mice via unilateral ureteral obstruction (UUO). Hypoxia‐induced HK‐2 cells were used to imitate the pathological process of renal fibrosis in vitro. Results showed that the treatment of AKBA significantly alleviated UUO‐induced impairment of renal function and improved the renal fibrosis by decreasing the expression of TGF‐β1, α‐SMA, collagen I and collagen IV in UUO kidneys. In hypoxia‐induced HK‐2 cells, AKBA displayed remarkable cell protective effects and anti‐fibrotic properties by increasing the cell viability, decreasing the lactate dehydrogenase (LDH) release and inhibiting fibrotic factor expression. Moreover, in obstructed kidneys and HK‐2 cells, AKBA markedly down‐regulated the expression of TGFβ‐RI, TGFβ‐RII, phosphorylated‐Smad2/3 (p‐Smad2/3) and Smad4 in a dose‐dependent fashion while up‐regulated the expression of Klotho and Smad7 in the same manner. In addition, the effects of AKBA on the Klotho/TGF‐β/Smad signalling were reversed by transfecting with siRNA‐Klotho in HK‐2 cells. In conclusion, our findings provide evidence that AKBA can effectively protect kidney against interstitial fibrosis, and this renoprotective effect involves the Klotho/TGF‐β/Smad signalling pathway. Therefore, AKBA could be considered as a promising candidate drug for renal interstitial fibrosis.

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Section: Discussionmentioning

confidence: 51%

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Liu

Shang

et al. 2018

J Cellular Molecular Medi

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“…7,15 Activation of TGF␤/Smad2,3 signaling during renal inflammation also produces a chemotatic effect on macrophages by inducing monocyte chemoattractant protein-1 (MCP-1)/ CCL2 expression. 16,17 Furthermore, urinary levels of TWEAK, a cytokine of the TNF superfamily, significantly increase and correlate with the activity of renal disease in patients with active lupus nephritis. 18 Exposure to TWEAK also induces MCP-1/CCL2, RANTES/CCL5, MIP-1␣/CXCL2, intraperitoneally-10/CXCL10, and SLC/CCL21 in MCs or tubular epithelial cells through a noncanonical NF-B pathway, thereby promoting leukocyte recruitment to the kidney during injury.…”

Section: Chemokines and Chemokine Receptorsmentioning

confidence: 99%

“…55,61,9 In unilateral ureteral obstruction (UUO) producing fibrosis, upregulation of tubulointerstitial MCP-1/ CCL2 correlates with degree of macrophage infiltration, which is associated with activation of the TGF␤/Smad3 signaling pathway. 16,17 TGF␤ signals through its downstream mediator, Smad3, to induce MCP-1 expression. Thus, mice deficient in Smad7, an inhibitor of TGF␤/Smad signaling, results inenhancedTGF␤/Smad3signalingthrough which MCP-1/CCL2-dependent macrophage infiltration and tubulointerstitial fibrosis develop in the UUO kidney.…”

Section: Role Of CCL and Cx3cl Chemokines In Chronic Kidney Diseasementioning

confidence: 99%

“…Thus, mice deficient in Smad7, an inhibitor of TGF␤/Smad signaling, results inenhancedTGF␤/Smad3signalingthrough which MCP-1/CCL2-dependent macrophage infiltration and tubulointerstitial fibrosis develop in the UUO kidney. 16 In contrast, inhibition or loss of TGF␤/Smad3 signalingblocksMCP-1expressionandmac-rophage accumulation in anti-GBM nephritis and UUO. 17,[62][63][64][65] Thus, upregulation of MCP-1/CCL2 and the development of macrophage accumulation in chronic kidney disease may be TGF␤/Smad3-dependent.…”

Section: Role Of CCL and Cx3cl Chemokines In Chronic Kidney Diseasementioning

confidence: 99%

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Chemokines in Renal Injury

Chung

Lan

2011

Journal of the American Society of Nephrology

239

181

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Renal inflammation underlies many chronic kidney diseases and the infiltration of leukocytes mediates much of the nephritogenic inflammatory response. As several recent reviews have dealt with the basic biology, mouse models, and blockade studies of chemokines in renal diseases, [1][2][3][4][5][6][7][8][9][10][11] we focus here on recent developments in pathophysiology of that chemokine effect. CHEMOKINES AND CHEMOKINE RECEPTORSChemokines are a group of chemotactic cytokines (approximately 8 to 17 kD) with the ability to bind G-proteincoupled receptors and act as potent attractants for leukocytes in acute and chronic inflammation. There are four subfamilies of chemokines, including CCL, CXCL, CX3CL, and CL (Figure 1). 7,6 At present, 19 receptors are known ( Figure 1). 6,7 The large CC chemokine family has the first two cysteine residues adjacent to each other, whereas the CXC family has a single amino acid residue in between the first two cysteines. Fractalkine (CX3CL1) is the only member of the CX3C chemokine family where three amino acid residues separate the first two cysteines. Finally, two related chemokines absent the two cysteine residues that bind the XCR1 receptor belong to the XC family. As shown in Figure 1, many chemokines bind multiple receptors and most receptors bind multiple chemokines. However, CC chemokine receptors exclusively bind CC chemokines and CXC receptors bind only CXC chemokines.Chemokines and their corresponding receptors are expressed in different cell types (Figure 2). 7,12 Generally speaking, monocytes are mostly attracted by CCL chemokines acting through CCR1, CCR2, andCCR5receptors,whereasneutrophilsare the target of CXCL chemokines through REGULATION OF CHEMOKINE EXPRESSIONOn the basis of their regulation and production, chemokines can be classified broadly as homeostatic/lymphoid or inflammatory chemokines. The former is responsible for leukocyte homing and ABSTRACTThe main function of chemokines is to guide inflammatory cells in their migration to sites of inflammation. During the last 2 decades, an expanding number of chemokines and their receptors have driven broad inquiry into how inflammatory cells are recruited in a variety of diseases. Although this review focuses on chemokines and their receptors in renal injury, proinflammatory IL-17, TGF␤, and TWEAK signaling pathways also play a critical role in their expression. Recent studies in transgenic mice as well as blockade of chemokine signaling by neutralizing ligands or receptor antagonists now allow direct interrogation of chemokine action. The emerging role of regulatory T cells and Th17 cells during renal injury also forges tight relationships between chemokines and T cell infiltration in the development of kidney disease. As chemokine receptor blockade inches toward clinical use, the field remains an attractive area with potential for unexpected opportunity in the future.

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“…This result was similar with that from some other reports. [19][20][21] TGF-β1/Smad3 signaling is a most important pathway leading to renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

All-Trans Retinoic Acid Attenuates the Renal Interstitial Fibrosis Lesion in Rats but Not By Transforming Growth Factor-β1/Smad3 Signaling Pathway

Zhou

Qin

et al. 2012

Renal Failure

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All-trans retinoic acid (ATRA) is an important therapeutic agent for prevention of the renal diseases. Transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway is a key signaling pathway which takes part in the progression of renal interstitial fibrosis (RIF). This investigation was performed to study the effect of ATRA in RIF rats and its effect on the TGF-β1/Smad3 signaling pathway. Sixty Wistar male rats were divided into three groups at random: sham operation group (SHO), model group subjected to unilateral ureteral obstruction (GU), model group treated with ATRA (GA), n ¼ 20, respectively. RIF index, protein expression of TGF-β1, collagen-IV (Col-IV) and fibronectin (FN) in renal interstitium, and mRNA and protein expressions of Smad3 in renal tissue were detected at 14-day and 28-day after surgery. The RIF index was markedly elevated in group GU than in SHO group (p < 0.01), and the RIF index of GA group was alleviated when compared with that in GU group (p < 0.01). Compared with in group SHO, the mRNA/protein expression of Smad3 in renal tissue was significantly increased in group GU (p < 0.01). However, the mRNA and protein expressions of Smad3 in renal tissue in GA group were not markedly alleviated by ATRA treatment when compared with those in GU (each p > 0.05). Protein expressions of TGF-β1, Col-IV, and FN in GU group were markedly increased than those in SHO group (each p < 0.01), and their expressions in GA group were markedly down-regulated by ATRA treatment than those of GU group (all p < 0.01). The protein expression of Smad3 was positively correlated with RIF index, protein expression of TGF-β1, Col-IV or FN (each p < 0.01). In conclusion, ATRA treatment can alleviate the RIF progression in UUO rats. However, ATRA cannot affect the signaling pathway of TGF-β1/Smad3 in the progression of RIF.

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Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice

Abstract: Smad7 is a critical negative regulator of TGF-beta/Smad2/3 and NF-kappaB signalling and plays a negative regulating role in both renal fibrosis and inflammation after UUO. Results from this study further support the notion that Smad7 may be a therapeutic agent for kidney diseases.

Cited by 168 publications

References 35 publications

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Chemokines in Renal Injury

All-Trans Retinoic Acid Attenuates the Renal Interstitial Fibrosis Lesion in Rats but Not By Transforming Growth Factor-β1/Smad3 Signaling Pathway

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