The overall objective of the proposed work is to use mathematical modeling to gain fundamental insights into the mechanisms by which nitric oxide (NO), superoxide (O2-), and heme oxygenase (HO) regulate renal medullary blood flow, oxygenation, and sodium reabsorption. We will develop numerical models, with inputs from experimental data, to investigate: (I) how NO and O2- regulate medullary thick ascending limb (mTAL) active sodium reabsorption and oxygen consumption. We will develop a new, steady-state model of vascular and tubular transport in the rat outer medulla (OM), that accounts for the three-dimensional architecture of the medulla, the presence of red blood cells, as well as the production and consumption of oxygen, NO and O2-. We will determine how interactions between NO and O2- affect mTAL sodium reabsorption under physiological and pathological conditions. We will examine the hypothesis that NO, as an endogenous inhibitor of active transport, plays an important role in modulating the susceptibility of the medulla to anoxic injury. (II) how NO and O2- regulate medullary blood flow, blood distribution, and oxygen supply. We will convert the new steady-state model into a dynamic model, and incorporate the effects of vasodilation on medullary blood flow (MBF). We will examine the hypothesis that the diffusion of paracrine substances such as NO from adjacent tubules to vasa recta pericytes provides an efficient mechanism whereby local perfusion is precisely matched to tubular oxygen demand. We will determine whether the enhancement of NO generation that is mediated by constrictors of the medullary circulation (such as Angiotensin II) may serve to protect the outer medulla from ischemic injury. (III) how renal medullary heme oxygenase (HO) and its products carbon monoxide (CO) and biliverdin modulate tubular sodium reabsorption and medullary blood flow. Recent evidence suggests that the renal medullary HO/CO system constitutes a significant antihypertensive mechanism. We will incorporate the activity of HO, the formation of its products, and their effects on reactive oxygen species and NO, first into a two- dimensional, steady-state model of the rat OM, then into the newly developed, three-dimensional, dynamic model. We will examine the hypothesis that significant expression of HO in the renal medulla serves to protect this region from ischemic injury, through CO-induced vasodilation and bilirubin-mediated antioxidant effects. We will simulate the effects of renal perfusion pressure-induced elevations in medullary CO concentrations on mTAL sodium reabsorption, so as to gain some insight into the mechanisms underlying pressure natriuresis.

Public Health Relevance

The objective of this proposal is to provide a better understanding of the mechanisms by which nitric oxide (NO), superoxide (O2-), and heme oxygenase (HO) regulate blood flow, oxygenation and sodium reabsorption in the renal medulla. This research is relevant to public health because NO, O2-, and HO all play an important role in the regulation of salt and water excretion by the kidney, and in the long-term control of arterial blood pressure. A shift in the balance between NO, O2-, and HO can lead to the progression of renal disease and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053775-12
Application #
8111089
Study Section
Special Emphasis Panel (ZRG1-RUS-C (02))
Program Officer
Ketchum, Christian J
Project Start
1999-07-15
Project End
2011-09-30
Budget Start
2011-07-01
Budget End
2011-09-30
Support Year
12
Fiscal Year
2011
Total Cost
$21,701
Indirect Cost
Name
Tufts University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
Sgouralis, Ioannis; Layton, Anita T (2012) Autoregulation and conduction of vasomotor responses in a mathematical model of the rat afferent arteriole. Am J Physiol Renal Physiol 303:F229-39
Edwards, Aurelie; Layton, Anita T (2011) Modulation of outer medullary NaCl transport and oxygenation by nitric oxide and superoxide. Am J Physiol Renal Physiol 301:F979-96
Edwards, Aurelie; Cao, Chunhua; Pallone, Thomas L (2011) Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta. Am J Physiol Renal Physiol 300:F441-56
Edwards, Aurélie (2010) A possible catalytic role for NH4+ in Na+ reabsorption across the thick ascending limb. Am J Physiol Renal Physiol 298:F510-1
Edwards, Aurelie; Layton, Anita T (2010) Nitric oxide and superoxide transport in a cross section of the rat outer medulla. I. Effects of low medullary oxygen tension. Am J Physiol Renal Physiol 299:F616-33
Loreto, Milagros; Layton, Anita T (2010) An optimization study of a mathematical model of the urine concentrating mechanism of the rat kidney. Math Biosci 223:66-78
Cao, Chunhua; Edwards, Aurélie; Sendeski, Mauricio et al. (2010) Intrinsic nitric oxide and superoxide production regulates descending vasa recta contraction. Am J Physiol Renal Physiol 299:F1056-64
Chen, Jing; Edwards, Aurelie; Layton, Anita T (2010) Effects of pH and medullary blood flow on oxygen transport and sodium reabsorption in the rat outer medulla. Am J Physiol Renal Physiol 298:F1369-83
Layton, Anita T; Edwards, Aurelie (2010) Tubuloglomerular feedback signal transduction in a short loop of henle. Bull Math Biol 72:34-62
Edwards, Aurelie (2010) Modeling transport in the kidney: investigating function and dysfunction. Am J Physiol Renal Physiol 298:F475-84

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