The microcirculation in the renal medulla plays an essential role in the regulation of fluid and electrolyte excretion and in the long-term maintenance of arterial blood pressure. The overall goal of this research is to extend our mathematical model of the renal medullary microcirculation in order to understand the effects of specific transporters, osmolytes and hormones on medullary blood flow and its distribution.
Our specific aims are as follows:
Aim 1 : To determine the importance of UTB urea transporters in providing a route for volume efflux that shunts blood flow from descending vasa recta (DVR) to ascending vasa recta (AVR), secondarily reducing blood flow to the inner medulla. We will incorporate new in vitro findings (including permeability and reflection coefficient measurements in UTB knockout mice) into our mathematical model in order to examine the role of water channels and urea transporters in regulating blood flow to the inner medulla.
Aim 2 : To examine the effects of the dependence of solute permeability on blood flow rate. Permeability of DVR to sodium and raffinose varies with perfusion rate; this dependence may be mediated by NO generation. We will investigate whether flow dependent increases in permeability reduce transmural concentration gradients and therefore water efflux from DVR, thereby enhancing blood flow to the inner medulla and decreasing concentrating ability.
Aim 3 : To determine whether lactate plays a significant role in the medullary microcirculation. It has been suggested that the accumulation of lactate could augment water removal from the thin descending limb and enable mathematical models to accurately predict cortico-medullary osmolality gradients. We will examine whether the presence of lactate can enhance volume efflux from DVR across transcellular pathways, thereby affecting blood flow to the papilla and axial small solute concentration gradients.
Aim 4 : To examine the effect of nitric oxide on overall medullary blood flow as well as on the distribution of blood flow between the inner medulla and the interbundle region of the outer medulla. We will investigate the extent to which NO generation may abrogate medullary hypoxia, and whether the production of nitric oxide by the thick ascending limb could constitute a feedback system aimed at specifically protecting the mTAL from ischemic injury, to the detriment of the inner medulla.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053775-09
Application #
7257792
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
1999-07-15
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
9
Fiscal Year
2007
Total Cost
$161,665
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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