Blockade of NFκB activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney  Yee-Yung Ng, Chun-Cheng Hou, Wansheng.

Slides:



Advertisements
Similar presentations
Volume 62, Pages S12-S22 (December 2002)
Advertisements

Volume 65, Issue 1, Pages (January 2004)
Volume 65, Issue 4, Pages (April 2004)
Volume 78, Issue 3, Pages (August 2010)
Volume 85, Issue 2, Pages (January 2014)
Latency-Associated Peptide Prevents Skin Fibrosis in Murine Sclerodermatous Graft- Versus-Host Disease, a Model for Human Scleroderma  Yan Zhang, Laura.
Volume 85, Issue 2, Pages (January 2014)
Volume 61, Issue 4, Pages (April 2002)
Smad7 gene transfer inhibits peritoneal fibrosis
MicroRNA-29b Inhibits Diabetic Nephropathy in db/db Mice
Volume 74, Issue 1, Pages (July 2008)
Volume 67, Issue 5, Pages (May 2005)
Volume 64, Issue 1, Pages (July 2003)
IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy  J.-A. Moon,
Volume 56, Pages S31-S36 (July 1999)
Volume 83, Issue 5, Pages (May 2013)
Volume 61, Issue 5, Pages (May 2002)
Volume 68, Issue 5, Pages (November 2005)
Volume 55, Issue 5, Pages (May 1999)
Volume 81, Issue 3, Pages (February 2012)
Volume 75, Issue 10, Pages (May 2009)
Volume 63, Issue 1, Pages (January 2003)
Volume 56, Issue 6, Pages (December 1999)
Volume 54, Issue 3, Pages (September 1998)
Volume 63, Issue 4, Pages (April 2003)
Paricalcitol attenuates cyclosporine-induced kidney injury in rats
Volume 59, Issue 5, Pages (May 2001)
Volume 59, Issue 4, Pages (April 2001)
Volume 81, Issue 3, Pages (February 2012)
Volume 56, Issue 3, Pages (September 1999)
Volume 81, Issue 9, Pages (May 2012)
Volume 56, Issue 2, Pages (August 1999)
Volume 65, Issue 2, Pages (February 2004)
Volume 63, Issue 5, Pages (May 2003)
Volume 57, Issue 2, Pages (October 2000)
Isotretinoin alleviates renal damage in rat chronic glomerulonephritis
Volume 81, Issue 3, Pages (February 2012)
Volume 58, Issue 1, Pages (July 2000)
Volume 62, Issue 2, Pages (August 2002)
The Rho-kinase pathway regulates angiotensin II-induced renal damage
Tight blood pressure control decreases apoptosis during renal damage
Volume 131, Issue 6, Pages (December 2006)
Volume 55, Issue 2, Pages (February 1999)
Volume 73, Issue 12, Pages (June 2008)
Volume 65, Issue 3, Pages (March 2004)
Jin H. Li, Xiao R. Huang, Hong-Jian Zhu, Richard Johnson, Hui Y. Lan 
Volume 63, Issue 4, Pages (April 2003)
Local macrophage proliferation in human glomerulonephritis
Volume 61, Issue 6, Pages (June 2002)
Volume 62, Pages S12-S22 (December 2002)
Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy  Carolina Lavoz, Yenniffer Sánchez Matus,
Volume 66, Issue 4, Pages (October 2004)
Volume 71, Issue 9, Pages (May 2007)
Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis  H.-C. Yang, L.-J. Ma, J. Ma, A.B. Fogo 
Volume 74, Issue 1, Pages (July 2008)
Volume 59, Issue 5, Pages (May 2001)
Volume 68, Issue 5, Pages (November 2005)
Knockdown of Stat3 activity in vivo prevents diabetic glomerulopathy
Volume 58, Issue 4, Pages (October 2000)
Volume 59, Issue 5, Pages (May 2001)
Volume 121, Issue 3, Pages (September 2001)
miR-29 Inhibits Bleomycin-induced Pulmonary Fibrosis in Mice
Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats
Volume 63, Issue 1, Pages (January 2003)
Jens Gaedeke, Nancy A. Noble, Wayne A. Border  Kidney International 
T-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis  Masashi Haraguchi, Wayne A. Border, Yufeng Huang,
Volume 21, Issue 2, Pages (February 2013)
J. Ma, A. Weisberg, J.P. Griffin, D.E. Vaughan, A.B. Fogo, N.J. Brown 
Volume 65, Issue 1, Pages (January 2004)
Volume 75, Issue 2, Pages (January 2009)
Presentation transcript:

Blockade of NFκB 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, Hui Y. Lan  Kidney International  Volume 67, Pages S83-S91 (April 2005) DOI: 10.1111/j.1523-1755.2005.09421.x Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 1 Effect of gene transfer of Smad7 on renal histologic damage in 5/6 nephrectomy in rats. (A) Sham-control, showing normal kidney histology. (B) Diseased kidney treated with empty vector controls exhibits focal severe tubulointerstitial damage, including many mononuclear cell infiltration and tubulointerstitial fibrosis. (C) Diseased kidney treated with Smad7 shows that renal histologic damage is prevented. Kidney sections are stained with PAS. Magnification: ×200. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 2 Immunohistochemistry shows that gene transfer of Smad7 inhibits leukocytic infiltration in the rat remnant kidney. (A–C) OX-1+ total leukocytes, (D–F) ED1+ macrophages, and (G–I) R73+ T cells in sham-operated rat kidney (A, D, G), empty control vector-treated (B, E, H), and Smad7-treated (C, F, I) kidney. Positive cells are shown in black. Each panel represents the staining pattern for groups of 6 rats. Magnification: ×200. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 3 Semiquantification of leukocytic infiltration in the rat remnant kidney. (A–C) Glomerular leukocytic infiltration, and (D–F) tubulointerstitial leukocytic infiltration for OX-1+ total leukocytes (A, D), ED1+ macrophages (B, E), and R73+ T cells (C, F) in sham-operated rat kidney (open bars), empty control vector-treated (solid bars), and Smad7-treated (hatched bars) kidney. Each bar represents the mean ± SEM for a group of 6 rats. **P < 0.01, ***P < 0.001. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 4 Real-time PCR shows that gene transfer of Smad7 inhibits IL-1β, TNFα, iNOS, and ICAM-1 mRNA expression in the rat remnant kidney. Total kidney RNA extracted from sham-operated rats (open bars), empty control vector-treated (solid bars), and Smad7-treated (hatched bars) rats were examined by real-time PCR for (A) IL-1β, (B) TNFα, (C) iNOS, and ICAM-1 levels. Each bar represents the mean ± SEM for a group of 6 rats. *P < 0.05, *P < 0.01, and **P < 0.001; ns, not significant. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 5 Immunohistochemistry shows that gene transfer of Smad7 inhibits IL-1β, iNOS, and ICAM-1 protein expression in the rat remnant kidney. Kidney sections from sham-operated rats (open bars), empty control vector-treated (solid bars), and Smad7-treated (hatched bars) rats were stained with antibodies against (A) IL-1β, (B) iNOS, and (C) ICAM-1 and quantitated using a quantitative Image Analysis System as described in Methods. Each bar represents the mean ± SEM for a group of 6 rats. *P < 0.05 and ***P < 0.001; ns, not significant. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 6 Immunohistochemistry shows that gene transfer of Smad7 inhibits NFκB/p65 activation in the rat remnant kidney. Kidney sections from (A, D) sham-operated rats, (B, E) empty control vector-treated, and (C, F) Smad7-treated rats were stained with antibodies against (A–C) NFκB/p65 and (D–F) p50 subunits and quantitated using quantitative a quantitative Image Analysis System as described in Methods. Note that numerous NFκB/p65+ cells (dark black nuclei) are evident in empty (B) control vector-treated kidney, which is completely inhibited by gene transfer of (C) Smad7. In contrast, there are no obvious changes in NFκB/p50 subunit in sham, control vector, or Smad7-treated animals (D, E). Semiquantitation of p65 subunit in both glomeruli and tubulointerstitium is shown in (G) and (H). Each bar represents the mean ± SEM for a group of 6 rats. *P < 0.05 and **P < 0.01. Magnification: ×250. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 7 Immunohistochemistry shows that gene transfer of Smad7 inhibits vascular NFκB/p65 activation, IL-1β expression, and macrophage accumulation in severe vascular proliferative lesions in the rat remnant kidney. Kidney sections from (A, D, G) sham-operated rats, (B, E, H) empty control vector-treated, and (C, F, I) Smad7-treated rats were stained with antibodies against (A–C) NFκB/p65, (D–F) IL-1β, and (G–I) ED-1. A set of serial sections (B, E) from empty control vector-treated kidney shows that marked vascular (v) NFκB/p65 activation (B, dark black nuclei) is associated with strong expression of IL-1β (E), resulting in severe proliferating vascular damage with much ED1+ macrophage accumulation (H). In contrast, Smad7 treatment completely blocks vascular NFκB/p65 activation (C), IL-β expression, and prevents macrophage accumulation (I). Magnification: ×400. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 8 The proposed cross-talk pathway of TGF-β/Smad7 and NFκB. Activation of the TGF-β signaling pathway can result in the expression of inhibitory Smad7. This inhibitory Smad appears to act by specifically inhibiting Smad2 and Smad3 phosphorylation via the negative-feedback loop to inhibit the fibrogenic effect of TGF-β. On the other hand, Smad7 may increase IkBα (a NFκB inhibitor) expression in response to TGF-β, thereby inhibiting NFκB activation and inflammatory response. Kidney International 2005 67, S83-S91DOI: (10.1111/j.1523-1755.2005.09421.x) Copyright © 2005 International Society of Nephrology Terms and Conditions