The renal proximal tubule (PT) plays an important role in homeostasis by reabsorption of salt and water and yet is often exposed to toxic and ischemic insults, and thus constantly undergoes injury and repair. Indeed, PT injury is a major cause of renal failure. PT contains a complete renin-angiotensin system (RAS) and produces endogenous angiotensin II (Ang II). Angiotensin converting enzyme inhibitor effectively slows progression of chronic renal insufficiency, and may ameliorate tubulointerstitial injury. Therefore, the RAS and its product, Ang II, may play an important role in PT injury and repair. The principal investigator proposes to use lines (that he has developed and characterized) of immortalized rat proximal tubule cells (IRPTC) from weanling rat kidney that express all the components of the RAS, including Ang II receptor subtypes AT1 and AT2, as a model. The studies will focus on the role of Ang II in PT injury and repair. The overall hypothesis is that PT injury involves modulation of both AT1 and AT2 in PT; furthermore, that AT1 receptor activation leads to cell growth and proliferation, while AT2 inhibits growth as well as AT1 expression, later leading to programmed cell death. Using an IRPTC oxidant injury model, the Specific Aims proposed will test the following hypotheses: 1) that PT injury initially upregulates both AT1 and AT2 expression; 2) that PT injury induces release of endogenous Ang II which influences subsequent transcription of both AT1 and AT2 receptors; and 3) that during repair there is crosstalk between AT2 and AT1, i.e., that AT2 receptor activation inhibits AT1 expression through intracellular Na+ loading, and later AT2 induces programmed cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK050836-01A2
Application #
2017118
Study Section
Special Emphasis Panel (ZRG4-GMB (04))
Project Start
1997-05-01
Project End
2001-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Hsieh, Tusty-Jiuan; Fustier, Pierre; Wei, Chih-Chang et al. (2004) Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells. J Endocrinol 183:535-50
Kiley, Susan C; Thornhill, Barbara A; Tang, Shiow-Shih et al. (2003) Growth factor-mediated phosphorylation of proapoptotic BAD reduces tubule cell death in vitro and in vivo. Kidney Int 63:33-42
Hsieh, Tusty-Jiuan; Fustier, Pierre; Zhang, Shao-Ling et al. (2003) High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells. Endocrinology 144:4338-49
Wang, Zhen; Garabedian, Michael J (2003) Modulation of glucocorticoid receptor transcriptional activation, phosphorylation, and growth inhibition by p27Kip1. J Biol Chem 278:50897-901
Zhang, Shao-Ling; To, Catherine; Chen, Xing et al. (2002) Essential role(s) of the intrarenal renin-angiotensin system in transforming growth factor-beta1 gene expression and induction of hypertrophy of rat kidney proximal tubular cells in high glucose. J Am Soc Nephrol 13:302-12
Zhang, Shao-Ling; Chen, Xing; Wei, Chih-Chang et al. (2002) Insulin inhibits dexamethasone effect on angiotensinogen gene expression and induction of hypertrophy in rat kidney proximal tubular cells in high glucose. Endocrinology 143:4627-35
S-L Zhang; Chen, X; Hsieh, T-J et al. (2002) Hyperglycemia induces insulin resistance on angiotensinogen gene expression in diabetic rat kidney proximal tubular cells. J Endocrinol 172:333-44
Yoshida, Takumi; Kurella, Manjula; Beato, Francisca et al. (2002) Monitoring changes in gene expression in renal ischemia-reperfusion in the rat. Kidney Int 61:1646-54
Hsieh, Tusty-Jiuan; Zhang, Shao-Ling; Filep, Janos G et al. (2002) High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology 143:2975-85
Zhang, S L; To, C; Chen, X et al. (2001) Effect of renin-angiotensin system blockade on the expression of the angiotensinogen gene and induction of hypertrophy in rat kidney proximal tubular cells. Exp Nephrol 9:109-17

Showing the most recent 10 out of 15 publications