It is now clear the progression of renal disease involves not only the glomerulus, but also the tubulointerstitial region. While many peptide growth factors, cytokines, and vasoactive hormones have been postulated to play an important role in the pathogenesis of progressive nephron destruction, there is potentially a central role for arachidonate products of cyclooxygenase. Because the collecting duct is both a major site for renal cyclooxygenase and prostaglandin synthesis and because numerous experimental models of renal injury have been associated with not only increased glomerular, but also urinary cyclooxygenase products, it would appear critical to investigate the role of collecting duct prostaglandin formation in a relevant model of progressive renal failure. This proposal is to elucidate those factors causing renal prostaglandin synthesis to increase after three-quarters nephrectomy in the rabbit. Studies will focus on the rabbit since monoclonal antibodies recently developed in our laboratory against the collecting duct of this species will allow biochemical characterization of collecting duct cells harvested post sub- total nephrectomy. Using both freshly immunodissected cells as well as cells placed in primary culture, we will examine prostaglandin synthesis, measure cyclooxygenase levels using immunoprecipitation, and cyclooxygenase message using norther blot analysis. We will also determine the effects of sub-total nephrectomy on the expression of P21-ras and P35 proteins that localize to the collecting duct and appear to critically interact with the process of cyclooxygenase product formation. These studies will be extended to examine the effects of increased prostaglandin levels or inhibition of endogenous prostaglandin synthesis on extracellular matrix formation by cultured medullary collecting duct cells and renal medullary interstitial cells. Finally, the effects of prostaglandins and their analogues on growth of cultured collecting duct and renal medullary interstitial cells will be determined. It is the goal of these studies to characterize for the first time the role of the collecting duct in generating prostaglandins after renal injury and the significance of this prostaglandin generation as it relates to functional and structural changes in the renal medulla. This information should open up new avenues for investigation of the progression of renal disease.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
He, Wenjuan; Zhang, Min; Zhao, Min et al. (2014) Increased dietary sodium induces COX2 expression by activating NF?B in renal medullary interstitial cells. Pflugers Arch 466:357-367
Fujita, Hiroki; Fujishima, Hiromi; Takahashi, Keiko et al. (2012) SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice. Metabolism 61:1714-24
Zent, Roy; Harris, Raymond (2012) The mammalian kidney. Exp Cell Res 318:v
Riggins, Karen S; Mernaugh, Glenda; Su, Yan et al. (2010) MT1-MMP-mediated basement membrane remodeling modulates renal development. Exp Cell Res 316:2993-3005
Fujita, Hiroki; Fujishima, Hiromi; Chida, Shinsuke et al. (2009) Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J Am Soc Nephrol 20:1303-13
Sparrow, Duncan B; Boyle, Scott C; Sams, Rebecca S et al. (2009) Placental insufficiency associated with loss of Cited1 causes renal medullary dysplasia. J Am Soc Nephrol 20:777-86
Zhang, Ming-Zhi; Xu, Jie; Yao, Bing et al. (2009) Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. J Clin Invest 119:876-85
Yao, Bing; Harris, Raymond C; Zhang, Ming-Zhi (2009) Intrarenal dopamine attenuates deoxycorticosterone acetate/high salt-induced blood pressure elevation in part through activation of a medullary cyclooxygenase 2 pathway. Hypertension 54:1077-83
Srichai, Manakan B; Hao, Chuanming; Davis, Linda et al. (2008) Apoptosis of the thick ascending limb results in acute kidney injury. J Am Soc Nephrol 19:1538-46
Boyle, Scott; Misfeldt, Andrew; Chandler, Kelly J et al. (2008) Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Dev Biol 313:234-45

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