Proteoglycans (PGs) are essential components of the extracellular matrices (glomerular basement membrane, GBM; mesangial matrix, MM), and apparently synthesized, in various proportions, by all the cell types o the renal glomerulus, i.e. epithelium, endothelium & mesangium. They impart charge- & size-selective properties to the glomerulus & maintain its integrity. Accordingly, structural derangements of the PGs, due to imbalance in their synthesis by different cell types of the glomerulus, would be expected to result in the disorganization of the extracellular matrices & proteinuria. Such structural alterations are seen in various immunologically & nonimmunologically mediated nephritides. We propose to delineate the pathogenetic mechanisms, relative to the proteoglycan biosynthesis, leading to such structural abnormalities by utilizing cell- biological biochemical, immunohistochemical & molecular biology techniques in the following four objectives: Objective I. cDNA probes for the rat GBM heparan sulfate-proteoglycan (HS- PG) will be prepared: following which nucleotide sequence determined & compared with the aminoacid sequence of the core-peptide of HS-PG. Objective II. Alterations in the proteoglycan biosynthesis at transcriptional & posttranslational levels will be investigated in immunologically & nonimmunologically-mediated glomerular nephritides by utilizing the above indicated techniques. Objective III. Effect of various inflammatory mediators, e,g., IL-I, PGA2, PGE2, TNF ROS; and glucocorticoids on the biosynthesis of PGs will be investigated in an organ perfusion system & by the techniques outlined above. Objective IV. Role of proteoglycans in renal glomerular development in vivo & in vitro states will be investigated by perturbing the metabolism at various steps of their biosynthesis with exposure to xyloside & puromycin. With these objectives we anticipate to delineate the breakdown in the cellular mechanisms & in the intricate balance of the biosynthesis of PGs by the various cell types of the glomerulus which lead to structural derangements in the extracellular matrices as observed in various nephritides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK028492-12
Application #
3228861
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-04-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
12
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
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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