Ang II plays a pivotal role in the development of end-stage renal disease. It is known that Ang II acts by stimulating TGF-b to mediate renal fibrosis. However, our preliminary studies showed an additional signaling pathway that may be required for renal fibrosis induced by Ang II. We found that Ang II is able to activate the TGF-b signaling pathway, Smad2 and SmadS. This response leads to increased collagen production by two mechanisms: 1) an acute pathway (5-30 minutes) via activation of the ERK/p38 MAP kinases; and 2) a late mechanism (24 hours) that acts through autocrine TGF-b and leads to fibrosis. Furthermore, we also find that mice null for SmadS are protected against renal fibrosis, while mice that are conditionally deleted for Smad2 enhance SmadS signaling and renal fibrosis in response to Ang II. Thus, we hypothesize that Smad signaling is a key to the development of renal fibrosis in response to Ang II. We plan to test this hypothesis and to determine the new role for the Ang Il-Smad signaling pathway in renal fibrosis by pursuing three specific aims.
In Aim 1, we will study that Ang II activates Smads via an acute (5-30 mins) ERK/p38 MAPKdependent and a late (20 hrs) classic TGF-b-dependent pathways.
In Aim 2, we will dissect the functional role of TGF-b-dependent and independent Smad signaling pathways in Ang ll-induced renal fibrosis in mesangial cells (MC) and tubular epithelial cells (TEC) that do or do not express TGF-b or TbRII, and in conditional TbRII KO mice.
In Aim 3, we will dissect the specific role of Smad2 or SmadS in Ang ll-mediated renal fibrosis. This will be examined in mouse embryonic fibroblasts, MC, and TEC that do or do not express Smad2 and SmadS and in SmadS KO and conditional Smad2 KO mice. We expect that the outcomes obtained from this study will support the central hypothesis and provide new insights into the pathogenesis of Ang ll-mediated renal fibrosis and valuable information for the development of new therapeutic strategies to combat renal fibrosis by targeting Smad signaling. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062828-01A2
Application #
6917412
Study Section
Special Emphasis Panel (ZRG1-RUS-E (02))
Program Officer
Flessner, Michael Francis
Project Start
2005-05-01
Project End
2010-03-31
Budget Start
2005-05-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$352,500
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Liping; Rajan, Vik; Lin, Eugene et al. (2011) Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J 25:1653-63
Wang, Huiling; Liu, Dajun; Cao, Peirang et al. (2010) Atrogin-1 affects muscle protein synthesis and degradation when energy metabolism is impaired by the antidiabetes drug berberine. Diabetes 59:1879-89
Hu, Zhaoyong; Wang, Huiling; Lee, In Hee et al. (2010) PTEN inhibition improves muscle regeneration in mice fed a high-fat diet. Diabetes 59:1312-20
Zhang, Liping; Wang, Xiaonan H; Wang, Huiling et al. (2010) Satellite cell dysfunction and impaired IGF-1 signaling cause CKD-induced muscle atrophy. J Am Soc Nephrol 21:419-27
Sheikh-Hamad, David (2010) Mammalian stanniocalcin-1 activates mitochondrial antioxidant pathways: new paradigms for regulation of macrophages and endothelium. Am J Physiol Renal Physiol 298:F248-54
Wang, Yanlin; Huang, Luping; Abdelrahim, Maen et al. (2009) Stanniocalcin-1 suppresses superoxide generation in macrophages through induction of mitochondrial UCP2. J Leukoc Biol 86:981-8
Hu, Zhaoyong; Wang, Huiling; Lee, In Hee et al. (2009) Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. J Clin Invest 119:3059-69
Zhang, Liping; Ran, Limei; Garcia, Gabriela E et al. (2009) Chemokine CXCL16 regulates neutrophil and macrophage infiltration into injured muscle, promoting muscle regeneration. Am J Pathol 175:2518-27
Huang, Luping; Garcia, Gabriela; Lou, Yahuan et al. (2009) Anti-inflammatory and renal protective actions of stanniocalcin-1 in a model of anti-glomerular basement membrane glomerulonephritis. Am J Pathol 174:1368-78
Zhang, Liping; Du, Jie; Hu, Zhaoyong et al. (2009) IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting. J Am Soc Nephrol 20:604-12

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