Oxidative stress contributes to cell injury in diabetic nephropathy (DN), a major complication of type 1 and type 2 diabetes. Diabetes is characterized by mitochondrial dysfunction which results in decreased activity of the respiratory chain complexes associated with enhanced generation of reactive oxygen species (ROS). Hyperglycemia contributes to mitochondrial dysfunction and oxidative stress. We have strong evidence that high glucose enhances cell hypertrophy and fibronectin expression in mesangial cells through the NAD(P)H- oxidase isoenzyme Nox4. In addition, Nox4-dependent ROS generation is increased within the renal cortex and isolated glomeruli of rats with streptozotocin-induced diabetes. We provide strong evidence that Nox4 is present not only in cell membranes but also in mitochondria. This suggests that in addition to the mitochondrial electron-transport chain (mtETC), Nox oxidases are a source of ROS in diabetes. The central hypothesis of this proposal is that Nox4 is activated by glucose in renal glomerular cells and that an interplay exists between Nox4 and the mtETC that results in hypertrophy and matrix accumulation.
Specific aim #1 : to investigate the mechanisms by which glucose activates Nox4 and mtETC and the role of these two sources of ROS in the activation of protein kinase C and NFKB resulting in hypertrophy and fibronectin expression in renal cells.
Specific aim #2 : to explore the role of Nox4- and mtETC-derived ROS and the activation of PKC and NFKB in the structural and functional changes of diabetic nephropathy in two rat models of type 1 and type II diabetes. This project seeks to identify the cellular and subcellular source(s) of ROS and explore mechanisms by which hyperglycemia and oxidants result in kidney injury. This should help identify specific antioxidants to treat progressive diabetic nephropathy. Diabetes and diabetic nephropathy are major causes of morbidity and mortality in the general population. Euglycemia is a difficult goal to achieve. Oxidative stress contributes to diabetic complications;however, the precise sources of oxygen radicals are not completely defined. It is our hope that identifying specific sources of oxygen radicals will allow targeted therapy to prevent diabetic nephropathy.
|Ford, Bridget M; Eid, Assaad A; Goýýz, Monika et al. (2013) ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice. Am J Physiol Renal Physiol 305:F323-32|
|Bera, Amit; Ghosh-Choudhury, Nandini; Dey, Nirmalya et al. (2013) NF?B-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation. Cell Signal 25:2575-86|
|Lee, Hak Joo; Mariappan, Meenalakshmi M; Feliers, Denis et al. (2012) Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells. J Biol Chem 287:4451-61|
|Das, Falguni; Ghosh-Choudhury, Nandini; Dey, Nirmalya et al. (2012) Unrestrained mammalian target of rapamycin complexes 1 and 2 increase expression of phosphatase and tensin homolog deleted on chromosome 10 to regulate phosphorylation of Akt kinase. J Biol Chem 287:3808-22|
|New, David D; Block, Karen; Bhandhari, Basant et al. (2012) IGF-I increases the expression of fibronectin by Nox4-dependent Akt phosphorylation in renal tubular epithelial cells. Am J Physiol Cell Physiol 302:C122-30|
|Shevalye, Hanna; Lupachyk, Sergey; Watcho, Pierre et al. (2012) Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology 153:1152-61|
|Debnath, Subrata; Thameem, Farook; Alves, Tahira et al. (2012) Diabetic nephropathy among Mexican Americans. Clin Nephrol 77:332-44|
|Abboud, Hanna E (2012) Mesangial cell biology. Exp Cell Res 318:979-85|
|Velagapudi, Chakradhar; Bhandari, Basant S; Abboud-Werner, Sherry et al. (2011) The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes. J Am Soc Nephrol 22:262-73|
|Zhang, Hua; Zhang, Hong-Mei; Wu, Li-Ping et al. (2011) Impaired mitochondrial complex III and melatonin responsive reactive oxygen species generation in kidney mitochondria of db/db mice. J Pineal Res 51:338-44|
Showing the most recent 10 out of 13 publications