Blockade of NFκB activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney

Ng, Yee‐Yung; Hou, Chun-Cheng; Wang, Wansheng; Huang, Xiao Ru; Lan, Hui‐Yao

doi:10.1111/j.1523-1755.2005.09421.x

Cited by 102 publications

(98 citation statements)

References 27 publications

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“…Beyond the antifibrotic effect of Smad7 in renal fibrosis, we have now shown that upregulation of Smad7 can also inhibit renal inflammation. This is consistent with the previous report that overexpression of Smad7 in T cells prevents cellmediated renal injury in anti-glomerular basement membrane glomerulonephritis and overexpression of Smad7 within the kidney inhibits renal inflammation in remnant kidney disease (38,39). Therefore, upregulation of Smad7 may be a key mechanism by which TGF-␤ exerts its protective role in renal fibrosis and inflammation.…”

Section: Discussionsupporting

confidence: 81%

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Wang¹,

Huang²,

Li³

et al. 2005

Journal of the American Society of Nephrology

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230

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TGF-␤ has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-␤ in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-␤1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-␤1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1␤, TNF-␣, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-␤1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-␤1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IB␣ and a suppression of NF-B activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-␤-NF-B cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IB␣ directly in a time-and dose-dependent manner, thereby inhibiting NF-B activation and NF-B-driven inflammatory response. In conclusion, latent TGF-␤ may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-B activation via the induction of IkB␣ may be the central mechanism by which latent TGF-␤ prevents renal inflammation.

show abstract

Section: Discussionsupporting

confidence: 81%

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Wang¹,

Huang²,

Li³

et al. 2005

Journal of the American Society of Nephrology

Self Cite

230

231

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show abstract

“…However, inhibition of immune-mediated kidney disease, particularly crescentic glomerulonephritis by overexpression of Smad7, is novel, although it is noted that expression of Smad7 is able to block renal inflammation in nonimmunologically mediated renal injury in a mouse obstructive kidney model and in a rat model of kidney disease (13)(14)(15)(16). It is generally believed that TGF-␤ is an anti-inflammatory cytokine and immune modulator (28).…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that the blockade of TGF-␤ by targeting the upstream of its signaling may cause inflammation, although fibrosis response is inhibited. This concern has been addressed by recent studies that blockade of downstream of the TGF-␤/ Smad signaling pathway by overexpressing Smad7 is able to inhibit both renal fibrosis and inflammation via the mechanisms of blocking both Smad2/3 and NF-B signaling pathways in rat remnant kidney and obstructive kidney disease (13)(14)(15)(16). However, it remains unknown whether blockade of the TGF-␤ pathway by Smad7 can inhibit immunologically induced kidney disease.…”

mentioning

confidence: 98%

“…Preparation of a mixture of doxycycline-regulated pTRE-m2Smad7-expressing plasmids and gene transfer into the kidney of mouse using the ultrasound-microbubble-mediated technique were used as described previously (13)(14)(15), with modification. Briefly, for achievement of doxycycline-induced (a tetracycline derivative) Smad7 transgene expression, a mixed solution that contained 200 g of pTRE-m2Smad7 and Tet-On plasmids and Optison (echocardiographic contrast microbubbles; Mallinckrodt, St. Louis, MO) at the ratio of 1:1 (vol:vol) in 300 l was co-transfected into the kidney via the tail vein followed by ultrasound treatment transcutaneously on the back of both sides of kidney location (Sonopuls 590, 1 MHz; Ernaf-Nonius, Delft, Netherlands).…”

Section: Modified Ultrasound-mediated Gene Transfer Of Inducible Smadmentioning

confidence: 99%

“…kit (Vector Laboratories, Burlingame, CA), or streptavidin-biotin peroxidase system (Dako) were then applied to the sections for 1 h. Sections were counterstained with hematoxylin or methyl green. Semiquantitative evaluations for staining were performed as described previously (15,17,18).…”

Section: Clinical and Pathologic Evaluationmentioning

confidence: 99%

See 2 more Smart Citations

Smad7 Gene Therapy Ameliorates an Autoimmune Crescentic Glomerulonephritis in Mice

Huang

Lan

et al. 2007

Journal of the American Society of Nephrology

113

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Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-␤/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-␤ signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 ؋ DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-B activation (P < 0.01), thereby inhibiting ␣-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1␤ and IL-6), adhesion molecule/ chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4 ؉ cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.

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Oleuropein protects against lipopolysaccharide‐induced sepsis and alleviates inflammatory responses in mice

et al. 2020

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Sepsis results from a major systemic inflammatory response and can induce disorders in multiple organs. The present study evaluated the potential protective effects of oleuropein (OLE) against hyperinflammatory responses during lipopolysaccharide (LPS)‐induced sepsis in mice. Sixty male Balb/c mice were randomly categorized into five groups of 12 animals each: control, intraperitoneally injected with OLE (50 mg/kg), injected with LPS (10 mg/kg, intraperitoneal), and two groups administered OLE (25 and 50 mg/kg) for 3 days prior to LPS injection. Twenty‐four hours after lipopolysaccharide injection, the animals were sacrificed. Serum, liver, and kidney tissue samples were collected for biochemical analyses, histopathological examinations, and investigation of inflammation‐related gene expression. OLE pretreatment significantly reduced liver damage parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) and kidney damage parameters (blood urea nitrogen, creatinine, and kidney injury molecule‐1) in the septic mice. OLE pretreatment ameliorated LPS‐induced liver and kidney histological changes. OLE significantly mitigated the increased levels of malondialdehyde in the liver and kidneys and reduced levels of reduced glutathione induced by LPS. LPS injection also resulted in increased expression of the proinflammatory cytokines (TNF‐α, IL‐1β, and IL‐6) and inflammation‐related genes (Nos2, Hmgb1, Mpo, Cd46, Map2k4, and Map2k7) in the hepatic and renal tissues. OLE reduced these expressions to ameliorate the inflammatory response. Moreover, OLE pretreatment enhanced the survival rate of septic mice. In conclusion, OLE alleviated the inflammatory response to protect against LPS‐induced sepsis in mice.

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Blockade of NFκB activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney

Cited by 102 publications

References 27 publications

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Smad7 Gene Therapy Ameliorates an Autoimmune Crescentic Glomerulonephritis in Mice

Oleuropein protects against lipopolysaccharide‐induced sepsis and alleviates inflammatory responses in mice

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