Angiotensin II (Angll) is a key regulator of blood pressure and renal function. Abnormalities in the regulation of Angll lead to hypertension (HTN) and chronic renal insufficiency (CRI), and therapies that block Angll are among the most effective in treating HTN and in delaying progression of CRI;indeed, the injurious effects of Angll now receive more attention than its physiological role. However, a limitation in our understanding of the mechanisms by which Angll exacerbate HTN and CRI arises from the fact that much of our knowledge is derived from studies that utilize pressor doses of Angll, in which Angll levels are many-fold higher than that seen in clinical scenarios. In the current proposal, we employ the chronic administration of sub-pressor doses of Angll (SP-Angll) which, while increasing intrarenal Angll levels, maintains circulating Angll within physiologic limits. SP-Angll is characterized by oxidant-dependent increases in renal vascular reactivity, blunting of salt-induced cortical hyperemia, and attendant salt-sensitive HTN;additionally, SP-Angll upregulates inflammatory chemokines (i.e. monocyte chemoattractant protein-1;MCP-1) which promote renal injury. However, SP-Angll also induces adaptive pathways (heme oxygenase-1;HO-1) which mitigate the deleterious effects of Angll, and in this regard, we recently found that SP-Angll-induced HO-1 conferred an unexpected acquired resistance to acute renal ischemic injury. Our overall goal is to uncover the mechanisms by which interactions between SP-Angll-induced MCP-1 /HO-1 determine the divergent effects of SP-Angll on acute and chronic renal injury, and salt-sensitive HTN. We propose 3 aims.
In AIM #1 we will test the hypothesis that SP-Angll upregulates MCP-1, which in turn modulates renal vascular function and causes salt-sensitivity.
In AIM #2 we will assess the interactions between MCP-1 and HO-1 in determining progression of chronic renal injury induced by SP-Angll, and their modulation by salt intake.
In AIM #3 we will examine the cellular and hemodynamic mechanisms by which SP-Angll induces acquired resistance to acute renal failure, with emphasis on HO-1-dependent pathways. In summary, this application addresses how a specific hormone, Angll, can influence the course of three distinct, but related common illnesses: HTN, CRI and acute renal failure. Specifically, we investigate the mechanisms by which Angll initiates inflammatory cascades (that promote HTN and CRI), while simultaneously generating factors that protect against acute injury. Understanding such mechanisms, may help uncover novel therapeutic strategies in the treatment of these disorders, the importance of which is underscored by the enormous medical and financial burden that these ailments impose on the healthcare system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073401-06
Application #
7858354
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Ketchum, Christian J
Project Start
2006-08-04
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
6
Fiscal Year
2010
Total Cost
$285,822
Indirect Cost
Name
University of Mississippi Medical Center
Department
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Arany, István; Clark, Jeb S; Reed, Dustin et al. (2013) The role of p66shc in taxol- and dichloroacetic acid-dependent renal toxicity. Anticancer Res 33:3119-22
Arany, Istvan; Clark, Jeb; Reed, Dustin K et al. (2013) Chronic nicotine exposure augments renal oxidative stress and injury through transcriptional activation of p66shc. Nephrol Dial Transplant 28:1417-25
Arany, Istvan; Clark, Jeb S; Reed, Dustin K et al. (2013) Role of p66shc in renal toxicity of oleic acid. Am J Nephrol 38:226-32
Chandrashekar, Kiran B; Fulop, Tibor; Juncos, Luis A (2012) Medical management and prevention of nephrolithiasis. Am J Med 125:344-7
Arany, Istvan; Clark, Jeb S; Reed, Dustin K et al. (2012) Cisplatin enhances interaction between p66Shc and HSP27: its role in reorganization of the actin cytoskeleton in renal proximal tubule cells. Anticancer Res 32:4759-63
Chandrashekar, Kiran; Lopez-Ruiz, Arnaldo; Juncos, Ramiro et al. (2012) The Modulatory Role of Heme Oxygenase on Subpressor Angiotensin II-Induced Hypertension and Renal Injury. Int J Hypertens 2012:392890
Arany, Istvan; Reed, Dustin K; Grifoni, Samira C et al. (2012) A novel U-STAT3-dependent mechanism mediates the deleterious effects of chronic nicotine exposure on renal injury. Am J Physiol Renal Physiol 302:F722-9
Arany, Istvan; Grifoni, Samira; Clark, Jeb S et al. (2011) Chronic nicotine exposure exacerbates acute renal ischemic injury. Am J Physiol Renal Physiol 301:F125-33
Arany, Istvan; Clark, Jeb S; Ember, Istvan et al. (2011) Epigenetic modifiers exert renal toxicity through induction of p66shc. Anticancer Res 31:3267-71
Fülöp, Tibor; Cosmin, Adrian; Juncos, Luis A (2011) Recurring extracorporeal circuit clotting during continuous renal replacement therapy resolved after single-session therapeutic plasma exchange. J Clin Apher 26:214-5

Showing the most recent 10 out of 18 publications