Basic Research In Progressive Glomerulonephritis
Kidney International (2005) 67, S83–S91; doi:10.1111/j.1523-1755.2005.09421.x
Blockade of NF
B activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney
YEE-YUNG NG, CHUN-CHENG HOU, WANSHENG WANG, XIAO R HUANG and HUI Y LAN
Section of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang Ming University; Department of Medicine, Taipei Medical University-Wan-Fang Hospital, Taipei, Taiwan; and Department of Medicine-Nephrology, Baylor College of Medicine, Houston, Texas
Correspondence: Dr Hui Y. Lan, Department of Medicine-Nephrology, Baylor College of Medicine, One Baylor Plaza, Alkek N520, Houston, TX 77030. E-mail:hlan@bcm.tmc.edu
Abstract
Blockade of NF
B activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney.
Background
Transforming growth factor-
(TGF-) in renal fibrosis has been well studied, but little attention has been paid to the potential role of TGF- in the resolution of renal inflammation. We hypothesize that TGF- exerts its anti-inflammation properties by stimulating its negative signaling pathway involving Smad7.
Methods
A rat remnant kidney model was treated with a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble (Optison)–mediated system. Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water. All animals were euthanized at week 4 for examination of inflammatory responses.
Results
Real-time polymerase chain reaction (PCR) and immunohistochemistry revealed that gene transfer of Smad7 resulted in a substantial inhibition of interleukin-1 (IL-1) and tumor necrosis factor 
(TNF) expression (all P < 0.01 vs. control). This was associated with the attenuation of histology damage, proteinuria, serum creatinine, and an increase in creatinine clearance (all P < 0.05). In addition, overexpression of Smad7 significantly inhibited renal inflammation, including ICAM-1, iNOS, and accumulation of macrophages and T cells in both glomeruli and tubulointerstitium. Furthermore, gene transfer of Smad7 also substantially blocked nuclear factor kappa B (NF
B) activation in the rat remnant kidney (P < 0.01).
Conclusion
TGF-/Smad7 signaling plays a critical role in the resolution of renal inflammation in rat remnant kidney model. Inhibition of NFB activation is a key mechanism by which Smad7 suppresses renal inflammation, which suggests a crosstalk pathway between NFB and Smad7. The ability of Smad7 to inhibit renal inflammation indicates that ultrasound-microbubble–mediated Smad7 gene therapy may represents a new therapeutic strategy for glomerulonephritis.
Keywords:
TGF- signaling, Smad7, renal inflammation, NFB, remnant kidney
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