A mathematical model of the mammalian collecting duct will be developed, comprised of cellular models of cortical, outer medullary and inner medullary segments. The model will represent Na+, K+, and acid/base transport under normal and pathological conditions, and will predict their renal excretion, given distal delivery. The initial focus will be parameter assignment for normal collecting duct function and during hormonal stimulation. Important redundancies have been identified in electrolyte transport pathways: luminal membrane Na+ flux via NaCl cotransport or Na+ -channel; H+ secretion via H+-ATPase or H+, K+-ATPase; peritubular base exit via c;-/HCO3- exchange or by means of NH4+ - NH3 recycling. This investigation will estimate these flux components, and identify experimental maneuvers which may be used to unambiguously conform these estimates. Particular attention will be paid to cell volume regulation, especially in inner medullary collecting duct, which can vary its Na+ transport rat from brisk reabsorption to secretion, and which faces a wide range in luminal fluid tonicity. Homeostatic control mechanisms have emphasized modulation of ion channel activity: luminal membrane Na+-channel and peritubular membrane K+ and C1- channels. Model simulations will examine feasibility of these proposed mechanisms, under both transient and steady state environmental perturbations., The second focus will be simulation of collecting duct dysfunction. In experimental models (ureteral obstruction, amiloride or lithium administration), specific segmental transport defects have been identified. The model will assess the adequacy of known defects to rationalize observed solute excretion patterns. Finally, the model will simulate clinical tests of distal nephron function (e.g. transtubular K+ gradient, impact of diuretics and impermeant anions on urinary pH). Such tests have traditionally been used to infer specific transport defects in patients with disorders of K+ metabolism or urinary acidification. This approach will be scrutinized by programming specific transport defects, subjecting the model to simulated testing, and assessing the ability to infer the defect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK029857-19
Application #
6177128
Study Section
Physiology Study Section (PHY)
Program Officer
Scherbenske, M James
Project Start
1981-08-01
Project End
2001-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
19
Fiscal Year
2000
Total Cost
$164,670
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Wang, Tong; Weinbaum, Sheldon; Weinstein, Alan M (2017) Regulation of glomerulotubular balance: flow-activated proximal tubule function. Pflugers Arch 469:643-654
Weinstein, Alan M (2017) A mathematical model of the rat kidney: K+-induced natriuresis. Am J Physiol Renal Physiol 312:F925-F950
Weinstein, Alan M (2016) Systems biology of the cortical collecting duct. J Physiol 594:5733-5734
Perez Bay, Andres E; Schreiner, Ryan; Benedicto, Ignacio et al. (2016) The fast-recycling receptor Megalin defines the apical recycling pathway of epithelial cells. Nat Commun 7:11550
Weinstein, Alan M (2015) A mathematical model of the rat nephron: glucose transport. Am J Physiol Renal Physiol 308:F1098-118
Nanami, Masayoshi; Lazo-Fernandez, Yoskaly; Pech, Vladimir et al. (2015) ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl- secretion. Am J Physiol Renal Physiol 309:F251-8
Terker, Andrew S; Zhang, Chong; McCormick, James A et al. (2015) Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 21:39-50
Nanami, Masayoshi; Pech, Vladimir; Lazo-Fernandez, Yoskaly et al. (2015) ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. II. Bafilomycin-sensitive H+ secretion. Am J Physiol Renal Physiol 309:F259-68
Du, Zhaopeng; Weinbaum, Sheldon; Weinstein, Alan M et al. (2015) Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport. Am J Physiol Renal Physiol 308:F839-47
Weinstein, Alan M (2015) A mathematical model of rat proximal tubule and loop of Henle. Am J Physiol Renal Physiol 308:F1076-97

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