Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes Mausumee Guha * ,1 , Zhong-Gao Xu † , David Tung ‡ , Linda Lanting † and Rama Natarajan † * Department of Pharmacology, Kalypsys Inc., San Diego, California, USA; † Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, California, USA; and ‡ Department of Pfizer Inc., St. Louis, Missouri, USA 1 Correspondence: Department of Pharmacology (Metabolic Diseases), Kalypsys Inc., 10420 Wateridge Circle, San Diego, CA 92121, USA. E-mail: mguha@kalypsys.com Diabetic nephropathy (DN) remains a major complication in both type 1 and type 2 diabetes. Systemic administration of antitransforming growth factor-ß (TGF-ß) antibody has shown some promise in mouse models of DN. However, chronic blockade of the multifunctional TGB-ß could be problematic. Several downstream effects of TGF-ß are mediated by connective tissue growth factor (CTGF), which is up-regulated in several renal cells and secreted in the urine in the diabetic state. Using murine models of DN (type 1 and type 2) and a CTGF antisense oligonucleotide (ASO) of novel chimeric chemistry, we evaluated the specific role of this target in DN. In the type 1 model of DN, C57BL6 mice were made diabetic using streptozotocin injections and hyperglycemic animals were treated with CTGF ASOs (20 mg/kg/2 qw) for 4 months. ASO, but not mismatch control oligonucleotide, -treated animals showed significant reduction in target CTGF expression in the kidney with a concomitant decrease in proteinuria and albuminuria. Treatment with the CTGF ASO for 8 wk reduced serum creatinine and attenuated urinary albuminuria and proteinuria in diabetic db/db mice, a model of type 2 DN. The ASO also reduced expression of genes involved in matrix expansion such as fibronectin and collagen (I and IV) and an inhibitor of matrix degradation, PAI-1, in the renal cortex, contributing to significant reversal of mesangial expansion in both models of DN. Pathway analyses demonstrated that diabetes-induced phosphorylation of p38 MAPK and its downstream target CREB was also inhibited by the ASO. Our results strongly suggest that blocking CTGF using a chimeric ASO holds substantial promise for the treatment of DN.—Guha, M., Xu, Z-G., Tung, D., Lanting, L., Natarajan, R. Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. Key Words: diabetic nephropathy • CTGF • glomerular mesangial cells • antisense oligonucleotide
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Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes
Guha, Mausumee; Xu, Zhong-Gao; Tung, David; Lanting, Linda; Natarajan, Rama
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, Volume 21 (12): 3355
Fed of American Socs for Experimental Biology – Oct 1, 2007
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