Diabetic kidney disease is characterized by early upregulation of matrix gene expression in glomeruli leading to mesangial matrix expansion, and early dysregulation of mesangial and vascular smooth muscle cells leading to glomerular hypefiltration and glomerular hypertrophy. Our lab has identified the growth factor TGFb to be important in both aspects of early diabetic kidney disease. The role of the Smad pathway has been found to be critical in mediating many of TGF-b's effects, and we have recently found that Smad4 is critical forTGF-b stimulation of the alpha 1 chain of type I collagen in mesangial cells. The intracellular IP3-gated calcium channel, the inositol 1,4,5-trisphosphate receptor (IP3R), is closely linked to numerous cellular processes, including contractile function. We have found that regulation of the IP3R by TGF-b is linked to vascular and glomerular dysfunction in early diabetes.
In aim I of our competitive renewal we propose to examine the role of the Smad4 pathway in a1(l) collagen gene regulation in the diabetic milieu in cell culture as well as in diabetic animal models. Our in vivo studies will utilize novel ultrasound mediated transfection techniques in rats and mice. In the second aim we will define the mechanisms of regulation of the IP3R by TGF-b and determine whether IP3R regulation feedbacks on Smad signaling, via a calcium entry dependent Cam kinase II pathway. In the third aim, we will examine whether transfection of IP3R restores normal calcium transients and IP3R-mitochondrial communication in cell culture, and prevents glomerular hypertrophy in animal models of diabetic kidney disease. The completion of this set of studies will provide a clear understanding of the role of Smad4 and IP3R in mediating characteristic changes of diabetic kidney disease and hopefully result in future therapies.
| 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 |
| 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 |
| Mathew, Anna V; Okada, Shinichi; Sharma, Kumar (2011) Obesity related kidney disease. Curr Diabetes Rev 7:41-9 |
| 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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