Isozymes of heme oxygenase (HO) convert heme to biliverdin and provide the dominant heme-degradative mechanisms in tissues. HO-1 is the inducible, while HO-2 is the constitutive, isoform; HO-3 possesses trivial heme-degrading activity. The study of HO attracts considerable interest because of the recognized protective and vasorelaxant actions of HO in general, and the ready inducibility of HO-1, in particular. This R0-1 competitive renewal continues the study of HO-1 as a protective response against renal injury and pursues findings made in the present cycle: a novel stimulus for HO-1 was identified in the kidney, and one with critical relevance to renal vasoconstriction, namely, angiotensin II. Additionally, two novel pathways that may contribute to the cytoprotective actions of HO-1 were uncovered: the suppressive effect of HO-1 on monocyte chemoattractant protein-1 (MCP- 1), a chemokine incriminated in renal inflammation, and the inductive effect of HO-1 on p21Cip1.WAF1.SDII a cyclin-dependent kinase inhibitor which is also anti-apoptotic. Thus, induction of HO-1, on the one hand, may vitiate pathways of renal injury (angiotensin IT-induced vasoconstriction, the upregulation of MCP-1), while, on the other, HO-I induction may recruit p21-dependent pathways of protection. Because of the importance of angiotensin II, MCP-l, and p21 as determinants of renal injury, our renewal application pursues three specific aims.
Aim I hypothesizes that the HO system is a countervailing one that opposes the systemic and renal vasoconstrictive actions of angiotensin II; studies in this aim alter the expression of the HO system by pharmacologic, antisense approaches, and gene delivery, and examine their effects on angiotensin TI-induced constriction.
Aim II hypothesizes that the HO system suppresses renal expression of MCP-1. Using in vitro and in vivo models for lipopolysaccharide-induced MCP-l expression, this aim examines the regulatory role of the HO system on MCP-1 expression, focusing on the redox-regulatory effect of HO on NF-kB, the latter transcription factor critically controlling MCP-1 expression.
Aim III hypothesizes that the HO system upregulates p21 which contributes to the protective actions of HO-1.
This aim delineates the role of the cell cycle-inhibitory, anti-apoptotic molecule, p21, as a transducer of the cytoprotective effects of HO-1. Our proposals thus explore mechanisms by which HO interrupts major pathways of injury (Aims I and II) as well as recruits pathways that safeguard the kidney (Aim III).

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 #
5R37DK047060-14
Application #
6892821
Study Section
Special Emphasis Panel (ZRG1-HEM-2 (02))
Program Officer
Wilder, Elizabeth L
Project Start
1993-08-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
14
Fiscal Year
2005
Total Cost
$326,101
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Nath, Karl A; Katusic, Zvonimir S (2017) Endothelin-A Receptor Antagonism Retards the Progression of Murine Sickle Cell Nephropathy. J Am Soc Nephrol 28:2253-2255
Kang, Lu; Grande, Joseph P; Hillestad, Matthew L et al. (2016) A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1. Am J Physiol Renal Physiol 310:F466-76
Nath, Karl A (2015) Models of Human AKI: Resemblance, Reproducibility, and Return on Investment. J Am Soc Nephrol 26:2891-3
Kang, Lu; Hillestad, Matthew L; Grande, Joseph P et al. (2015) Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo. Am J Physiol Heart Circ Physiol 308:H1402-13
Belcher, John D; Chen, Chunsheng; Nguyen, Julia et al. (2014) Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123:377-90
Nath, Karl A (2014) Heme oxygenase-1 and acute kidney injury. Curr Opin Nephrol Hypertens 23:17-24
Kang, Lu; Grande, Joseph P; Farrugia, Gianrico et al. (2013) Functioning of an arteriovenous fistula requires heme oxygenase-2. Am J Physiol Renal Physiol 305:F545-52
Nath, Karl A; Grande, Joseph P; Farrugia, Gianrico et al. (2013) Age sensitizes the kidney to heme protein-induced acute kidney injury. Am J Physiol Renal Physiol 304:F317-25
Abudiab, Muaz; Krause, Megan L; Fidler, Mary E et al. (2013) Differentiating scleroderma renal crisis from other causes of thrombotic microangiopathy in a postpartum patient. Clin Nephrol 80:293-7
Nath, Karl A (2013) The role of renal research in demonstrating the protective properties of heme oxygenase-1. Kidney Int 84:3-6

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