Transforming growth factor-beta (TGF-beta) has been recently recognized to be a pivotal factor in mediating excessive matrix deposition in many disease states, including diabetic nephropathy. Studies from this group have demonstrated that TGF-beta activity attenuates high glucose-induced matrix stimulation in mesangial cells in vitro, attenuates diabetes-induced matrix accumulation and glomerular hypertrophy in vivo, and in recent data attenuates progression of renal failure. Diabetic glomerular disease has been associated with mesangial matrix accumulation, altered intracellular calcium mobilization, and abnormal vascular regulation. As TGF-beta promotes matrix synthesis and regulates intracellular calcium in mesangial cells, this group postulates that TGF-beta plays an important role in both diabetes-induced matrix accumulation and altered glomerular vasoregulation. The intracellular signaling pathways employed by TGF-beta in mesangial cells which underlie these effects are the focus of the current application. Several candidate pathways have been found to be stimulated by TGF-beta, the best characterized being the Smad pathway; however the relationship of the Smad pathway to matrix stimulation has not been established. Recent studies by this group have demonstrated that TGF-beta stimulates protein kinase A (PKA) activity in mesangial cells without raising intracellular cyclic AMP levels. The precise mechanisms of TGF-beta induced stimulation of PKA will be established. Dr. Sharma will also examine whether TGF-beta induced PKA activation and Smad activation are of importance in stimulating extracellular matrix molecules. One consequence of TGF- beta-induced PKA activation appears to be phosphorylation and down-regulation of the type I inositol 1.4.5-trisphosphate receptor (IP3R), the IP3, gated intracellular calcium channel. Additional studies have demonstrated that TGF-beta reduces protein expression of both types I and III IP3R isoforms. The mechanisms underlying TGF-beta induced regulation of the IP3Rs will be explored. The functional consequences of reduced IP3R expression in mesangial cells will be evaluated by measuring IP3 sensitivity and intracellular calcium mobilization in both intact and permeabilized cells. As TGF-beta is over-expressed by mesangial cells cultured in high glucose and in the glomeruli of diabetic rats, Dr. Sharma proposes to evaluate whether TGF-beta induced PKA activation and TGF-beta-induced IP3R regulation play important roles in diabetes-induced glomerular matrix production and altered reactivity of glomerular mesangial cells to vasoconstrictors in both in vitro and in vivo models. Understanding these pathways will lead to rational designs for interventional strategies to block specific TGF-beta-induced effects that contribute to the pathogenesis of diabetic nephropathy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Meyers, Catherine M
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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Bánsághi, Száva; Golenár, Tünde; Madesh, Muniswamy et al. (2014) Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species. J Biol Chem 289:8170-81
You, Young-Hyun; Okada, Shinichi; Ly, San et al. (2013) Role of Nox2 in diabetic kidney disease. Am J Physiol Renal Physiol 304:F840-8
Dugan, Laura L; You, Young-Hyun; Ali, Sameh S et al. (2013) AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest 123:4888-99
Diamond-Stanic, Maggie K; You, Young H; Sharma, Kumar (2012) Sugar, sex, and TGF-? in diabetic nephropathy. Semin Nephrol 32:261-8
Mathew, Anna V; Okada, Shinichi; Sharma, Kumar (2011) Obesity related kidney disease. Curr Diabetes Rev 7:41-9
Declèves, Anne-Emilie; Mathew, Anna V; Cunard, Robyn et al. (2011) AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol 22:1846-55
Sanchez, Amber P; Zhao, JingHong; You, Young et al. (2011) Role of the USF1 transcription factor in diabetic kidney disease. Am J Physiol Renal Physiol 301:F271-9
Vallon, Volker; Sharma, Kumar (2010) Sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Curr Opin Nephrol Hypertens 19:425-31
Calhoun, David A; Sharma, Kumar (2010) The role of aldosteronism in causing obesity-related cardiovascular risk. Cardiol Clin 28:517-27
Ix, Joachim H; Sharma, Kumar (2010) Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol 21:406-12

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