Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-β signaling and fibrosis in rat remnant kidney

TY - JOUR

T1 - Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-β signaling and fibrosis in rat remnant kidney

AU - Hou, Chun-Cheng

AU - Wang, Wansheng

AU - Huang, Xiao R.

AU - Fu, Ping

AU - Chen, Tso Hsiao

AU - Sheikh-Hamad, David

AU - Lan, Hui Y.

PY - 2005/3

Y1 - 2005/3

N2 - Transforming growth factor (TGF)-β1 has been shown to play a critical role in hypertensive nephropathy. We hypothesized that blocking TGF-β1 signaling could attenuate renal fibrosis hi a rat model of remnant kidney disease. Groups of six rats were subjected to 5/6 nephrectomy and received renal arterial injection of a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble-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 renal functional and histological examination. Hypertension of equivalent magnitude (190 to 200 mmHg) developed hi both Smad7- and empty vector-treated rats. However, treatment with Smad7 substantially inhibited Smad2/3 activation and prevented progressive renal injury by inhibiting the rise of 24-hour proteinuria (P <0.001) and serum creatinine (P <0.001), preserving creatinine clearance (P <0.05), and attenuating renal fibrosis and vascular sclerosis such as collagen I and III expression (P <0.01) and myofibroblast accumulation (P <0.001). In conclusion, TGF-β/Smad signaling plays a critical role in renal fibrosis in a rat remnant kidney model. The ability of Smad7 to block Smad2/3 activation and attenuate renal and vascular sclerosis demonstrates that ultrasound-mediated Smad7 gene therapy may be a useful therapeutic strategy for the prevention of renal fibrosis in association with hypertension.

AB - Transforming growth factor (TGF)-β1 has been shown to play a critical role in hypertensive nephropathy. We hypothesized that blocking TGF-β1 signaling could attenuate renal fibrosis hi a rat model of remnant kidney disease. Groups of six rats were subjected to 5/6 nephrectomy and received renal arterial injection of a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble-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 renal functional and histological examination. Hypertension of equivalent magnitude (190 to 200 mmHg) developed hi both Smad7- and empty vector-treated rats. However, treatment with Smad7 substantially inhibited Smad2/3 activation and prevented progressive renal injury by inhibiting the rise of 24-hour proteinuria (P <0.001) and serum creatinine (P <0.001), preserving creatinine clearance (P <0.05), and attenuating renal fibrosis and vascular sclerosis such as collagen I and III expression (P <0.01) and myofibroblast accumulation (P <0.001). In conclusion, TGF-β/Smad signaling plays a critical role in renal fibrosis in a rat remnant kidney model. The ability of Smad7 to block Smad2/3 activation and attenuate renal and vascular sclerosis demonstrates that ultrasound-mediated Smad7 gene therapy may be a useful therapeutic strategy for the prevention of renal fibrosis in association with hypertension.

UR - http://www.scopus.com/inward/record.url?scp=14644431025&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14644431025&partnerID=8YFLogxK

M3 - Article

C2 - 15743788

AN - SCOPUS:14644431025

VL - 166

SP - 761

EP - 771

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 3

ER -