The overall objective of this project is mathematical modeling and computer simulation of fluid and electrolyte disorders in kidney tubules. To date, this project has formulated models of proximal convoluted tubule, and all segments from distal convoluted tubule through cortical, outer medullary, and inner medullary collecting ducts. In the next investigational period, the first objective is to model the thick ascending Henle limb (AHL), both as an isolated tubule, and within the context of distal nephron function. The distal nephron model will be used to examine the proposal that medullary interstitial potassium concentration may control overall renal potassium and acid excretion, by modulating sodium delivery to distal tubule and collecting duct. Disorders of acid/base balance may derive from abnormal AHL function. Specifically, decreased AHL function with hyperkalemia has been implicated in the impaired ammonium excretion of hypoaldosteronism. Decreased AHL function is also the key feature of Bartter's syndrome, a disorder associated with metabolic alkalosis. Models will be used to characterize segmental contributions to acid excretion in each of these conditions. The second objective is to integrate all of the segmental models (adding proximal straight tubule and thin Henle limbs) into full nephrons. Initially, these will be solved against a prescribed interstitial composition, to examine luminal interactions among the segments, but ultimately interstitial variables must be solved in order to simulate tubular modification of the peritubular environment. Major metabolic derangements, such as hyperkalemia and acidosis, have been shown to alter renal medullary solutes and thus influence urine composition;this will be the first effort to simulate that impact. The third objective will be the application of control theory to the AHL model, in order to identify the modulated transporters responsible for cellular homeostasis, specifically, mechanisms used to accommodate large reabsorptive fluxes of sodium and ammonium, while preserving cell volume and pH. Genetic disorders of electrolyte metabolism or pharmacologic intervention will generally affect a single transporter in a single kidney tubule. However, the impact on overall kidney function may be far-reaching, affecting other segments, both adjacent and at a distance. Models such as these can explain the pattern of whole-organ malfunction as the consequence of a molecular defect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK029857-27
Application #
7652510
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
1981-08-01
Project End
2012-08-31
Budget Start
2010-01-01
Budget End
2012-08-31
Support Year
27
Fiscal Year
2010
Total Cost
$194,668
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
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
Wen, Donghai; Cornelius, Ryan J; Rivero-Hernandez, Dianelys et al. (2014) Relation between BK-?/?4-mediated potassium secretion and ENaC-mediated sodium reabsorption. Kidney Int 86:139-45
Weinstein, Alan M (2014) The diabetic proximal tubule: part of the problem, and part of the solution? Am J Physiol Renal Physiol 307:F147-8

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