Diabetic nephropathy is one of the major complications of diabetes, where cellular dysfunctions induced by hyperglycemia have certain degree of similarities in different compartments of the kidney, i.e., glomerular vs tubulo-interstitial or vascular. The cells affected may be derived from epithelial or mesenchymal progenitors;and at times hyperglycemia may induce a phenotypic change with epithelial-mesenchymal transformation. In target cells the high glucose activates various intracellular pathways that are similar except for minor variations. These pathways have been mainly studied in various cell types of the glomerulus, while the information available in the literature for the tubular compartment is limited. Intriguingly, our suppression subtraction analyses of kidneys of """"""""neonatal"""""""" diabetic mice indicate that the majority of the differentially up- regulated genes are expressed in the renal tubules, e.g., GTP binding protein Rap1b, guanine nucleotide exchange factor Epac1 and ubiquitin fusion protein UbA52 and etc. The Rap1b was found to exert downstream effects leading to up-regulation of extracellular matrix (ECM) proteins. Interestingly, the co- expressed Epac1 happens to positively regulate the Rap1b activity. A recently described negative regulator of Rap1b is Cbl, a proto-oncogene. All the three molecules are modulated by high glucose ambience. Conceivably, both Cbl and Epac1 exert their effects on Rap1b to strike a balance in its activity to dampen the complications of diabetes related to ECM biology. To attest to this contention various experiments are proposed under the following specific aims: I. Modulation of Rap1b, Cbl and Epac1 expression in animal models of diabetes will be investigated and correlated with the disease activity. Attempts will be made to gauge the activity of Rap1b on the expression of tubulo-interstitial ECM proteins. II. Effect of high glucose ambience on their expression will be investigated in cell culture systems. Efforts will be devoted to tease out the modulation of Rap1b by Cbl/Epac1 under high glucose by employing various agonists, inhibitors, dominant constructs &shRNA/siRNA oligos. III. Mechanism(s) by which high glucose activate, directly or indirectly, Cbl and Epac1, will be investigated by carrying out promoter analysis, gel shift and chromatin immunoprecipitation assays. Role of glycative, oxidant/antioxidant and osmotic stresses in their activation will be investigated. IV. Other molecules that could activate Rap1b will be identified by using co-immuno- precipitation procedures and yeast-two-hybrid systems. V. Since Epac1 is up-regulated in the """"""""neonatal"""""""" diabetic mice and exhibits differential expression during development, its modulation of nephrogenesis under high glucose ambience will be investigated. It is hoped that these studies would enhance our understanding of the """"""""Renal Tubulo-interstitial ECM Pathobiology"""""""" relevant to diabetic nephropathy.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rys-Sikora, Krystyna E
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Northwestern University at Chicago
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Sharma, Isha; Dutta, Rajesh K; Singh, Neel K et al. (2017) High Glucose-Induced Hypomethylation Promotes Binding of Sp-1 to Myo-Inositol Oxygenase: Implication in the Pathobiology of Diabetic Tubulopathy. Am J Pathol 187:724-739
Dutta, Rajesh K; Kondeti, Vinay K; Sharma, Isha et al. (2017) Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI. J Am Soc Nephrol 28:1421-1436
Wysocki, Jan; Ye, Minghao; Khattab, Ahmed M et al. (2017) Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy. Kidney Int 91:1336-1346
Yang, Shikun; Zhao, Li; Han, Yachun et al. (2017) Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc. Redox Biol 13:482-497
Nagasu, Hajime; Satoh, Minoru; Kiyokage, Emi et al. (2016) Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice. Lab Invest 96:25-36
Sun, Lin; Dutta, Rajesh K; Xie, Ping et al. (2016) myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience: A NEW MECHANISM RELEVANT TO THE PATHOGENESIS OF DIABETIC NEPHROPATHY. J Biol Chem 291:5688-707
Tominaga, Tatsuya; Dutta, Rajesh K; Joladarashi, Darukeshwara et al. (2016) Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids: IMPLICATIONS IN RENAL TUBULAR INJURY INDUCED IN OBESITY AND DIABETES. J Biol Chem 291:1348-67
Zhu, Xuejing; Xiong, Xiaofen; Yuan, Shuguang et al. (2016) Validation of the interstitial fibrosis and tubular atrophy on the new pathological classification in patients with diabetic nephropathy: A single-center study in China. J Diabetes Complications 30:537-41
Hu, C; Sun, L; Xiao, L et al. (2015) Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy. Curr Med Chem 22:2858-70
Zhan, Ming; Usman, Irtaza M; Sun, Lin et al. (2015) Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. J Am Soc Nephrol 26:1304-21

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