Hemodialysis vascular access dysfunction is considered the single most important issue in the care of the patient with endstage renal failure. Yet our understanding of the pathogenesis of vascular access dysfunction is poor, to a large extent, because of the lack of availability of relevant models amenable to investigation. The PI has demonstrated that the venous limb of an aorto-caval fistula in the rat recapitulates changes seen in dysfunctional dialysis arteriovenous fistulae (AVFs): neointima formation, angiogenesis, thrombosis, smooth muscle cell proliferation, and matrix expansion; these changes in this model are preceded by massive upregulation of MCP-1 (monocyte chemoattractant protein-1), the latter being one of the most important chemokines in vascular injury, and an independent risk factor for the dysfunction of clinical AVFs. MCP-1 can be downregulated by mechanisms which include heme oxygenase-1 (HO-1), a heme-degrading, vasoprotective, and anti-inflammatory enzyme. This application examines the significance of MCP-1 upregulation in this AVF model, and whether HO-dependent strategies can inhibit MCP-1 and intimal hyperplasia.
Aim I hypothesize that, and examine whether, clinically relevant mechanisms account for MCP-1 upregulation and intimal hyperplasia.
Aim II hypothesizes that MCP-1 upregulation is a determinant of intimal hyperplasia, and employs strategies which interrupt MCP-1 or its receptor.
Aim III determines whether HO induction or specific HO products/effectors inhibit MCP-1 expression and intimal hyperplasia.
Aim I V hypothesizes that venous remodeling in the AVF involves MCP-1-dependent recruitment of circulating and bone marrow-derived cells, and analyzes the origin of cells in the AVF by immunophenotyping, bone marrow transplantation, and adoptive cell transfer. In aggregate, these studies will determine the basis for and the pathogenetic significance of such upregulation of MCP-1, and may suggest strategies for preventing dysfunction of AVFs.
| Nath, Karl A; Allon, Michael (2017) Challenges in Developing New Therapies for Vascular Access Dysfunction. Clin J Am Soc Nephrol 12:2053-2055 |
| 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 |
| Nath, Karl A (2016) Dialysis Vascular Access Intervention and the Search for Biomarkers. J Am Soc Nephrol 27:970-2 |
| 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; Katusic, Zvonimir S (2016) Predicting the Functionality and Form of a Dialysis Fistula. J Am Soc Nephrol 27:3508-3510 |
| 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 |
| 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 |
| Tsapenko, Mykola V; d'Uscio, Livius V; Grande, Joseph P et al. (2012) Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula. Am J Physiol Renal Physiol 303:F1601-7 |
| Kang, Lu; Yamada, Satsuki; Hernandez, Melissa C et al. (2011) Regional and systemic hemodynamic responses following the creation of a murine arteriovenous fistula. Am J Physiol Renal Physiol 301:F845-51 |
Showing the most recent 10 out of 22 publications
