The overall objective of this proposal is to study the pathogenetic mechanisms involved in diabetic induced lesions in the embryonic metanephros. Three potential target genes will be examined mesodermal specific cDNA(MEST), H19, and TIN-Ag based on the spatio-temporal expression of these genes with MEST expressed in the metanephric mesenchyme H19 in the ureteric bud epithelia and TIN-Ag in an anti-polar proximal expression opposite that of H19 in the S-shaped body suggesting the three molecules are interlinked in early nephric development. Experiments are proposed under five specific aims to study the normal and abnormal biology of these molecules during renal development. I. Spatio-temporal expression of MEST, H19 and TIN-Ag during metanephric development will be investigated by using in situ hybridization, competitive PCR, immunohistochemical and immunoprecipitation methods. II. Their role in epithelial: mesenchymal interactions, prevalent during metanephrogenesis, will be assessed by antibody, antisense, transgene and transfection experiments. III. Molecular protein: protein and RNA: protein interactions will be investigated by using recombinant fusion proteins of various constructs of these three molecules. IV. Alterations in these molecules will be investigated during elevated concentration of glucose in vitro and in hyperglycemia. V. Finally, the hyperglycemia-induced/suppressed genes during embryonic renal development will be investigated using RDA and Serial Analysis of Gene Expression (SAGE).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DK028492-18
Application #
2855297
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-04-01
Project End
2003-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
18
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kanwar, Yashpal S; Sun, Lin; Xie, Ping et al. (2011) A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol 6:395-423
Wada, Jun; Sun, Lin; Kanwar, Yashpal S (2011) Discovery of genes related to diabetic nephropathy in various animal models by current techniques. Contrib Nephrol 169:161-74
Sun, Lin; Xiao, Li; Nie, Jing et al. (2010) p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway. Am J Physiol Renal Physiol 299:F1014-25
Zhu, Xuejing; Ling, Guanghui; Xiao, Li et al. (2010) Role of mitochondrial respiratory chain complex III in high glucose peritoneal dialysate-induced hyperpermeability of HPMCs. Ren Fail 32:1103-8
Zhang, Dongshan; Sun, Lin; Xian, Wang et al. (2010) Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-beta/Smad activity. Lab Invest 90:436-47
Kanwar, Yashpal S (2010) Revisiting basement membrane pathology in renal cystic disease. J Am Soc Nephrol 21:548-9
Xie, Ping; Sun, Lin; Oates, Peter J et al. (2010) Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis. Am J Physiol Renal Physiol 298:F1393-404
Bhalodia, Yagnik; Sheth, Navin; Vaghasiya, Jitendra et al. (2010) Role of fenofibrate alone and in combination with telmisartan on renal ischemia/reperfusion injury. Ren Fail 32:1088-94
Xie, Ping; Sun, Lin; Nayak, Baibasawata et al. (2009) C/EBP-beta modulates transcription of tubulointerstitial nephritis antigen in obstructive uropathy. J Am Soc Nephrol 20:807-19
Kanwar, Yashpal S; Sun, Lin (2008) Shuttling of calcium between endoplasmic reticulum and mitochondria in the renal vasculature. Am J Physiol Renal Physiol 295:F1301-2

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