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 glomerulus, proximal convoluted tubule, and all segments from ascending Henle limb, through distal tubule, and collecting duct. In the next investigational period, the first task is to complete the library of renal segmental models, and fashion short- and long-looped nephrons, solved against interstitial composition. These models will simulate axial interaction among segments, as in osmotic diuresis or acetazolamide action, and predict the impact of medullary K+ concentration on distal solute delivery. Solved iteratively, this model will allow representation of the stabilization of distal solute delivery via tubuloglomerular feedback.
The second aim will require the major investment of effort for the project period, and this will be to advance the nephron models from a specified interstitium to solving for interstitial concentrations as unknown variables. This aspect of the project is critical to estimating the impact of changing flows and changing transport on peritubular conditions. It extends the classical computational approach to the urine concentrating mechanism, to K+ and acid-base metabolism. Major metabolic derangements, such as hyperkalemia and acidosis, alter renal medullary solutes and thus influence urine composition;this will be the first effort to simulate that impact.
The third aim will be to examine cellular homeostasis as a systems approach to cell membrane transporters. The approach will use mathematical control theory to identify transporter ensembles, which can function in a coordinated way to allow large re-absorptive fluxes, while preserving cell volume and composition. These transporter ensembles maybe viewed as "hypothesis generation" with respect to experimental examination of kidney tubules. Finally, experimental collaborations are in progress to examine predictions from this project. Work continues with Dr. Tong Wang to examine flow-dependent proximal tubule transport, specifically our proposal that brush border microvilli are flow mechanosensors. Anew project is planned with Dr. Wang to examine flow-dependent transport in distal nephron, specifically in relation to flow-dependent HCO-3 re-absorption as a consequence of diuretic ad- ministration. Genetic disorders of electrolyte metabolism or pharmacologic intervention general- ly affect a single transporter in a single kidney tubule. However, the impact on overall kidney function maybe far-reaching, affecting other segments, both adjacent and at a distance. Such models can rationalize whole-organ malfunction as the consequence of a molecular defect.

Public Health Relevance

The overall objective of this project is mathematical and computer modeling of fluid and electrolyte disorders in kidney tubules. Hypertension and edema maybe due in part to excessive sodium absorption in one or more regions of the kidney, and treatment of sodium retention with diuretics can have adverse effects on blood levels of potassium and bicarbonate. This modeling effort will provide a tool for simulation of both the disorders and their treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK029857-28A1
Application #
8370374
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Ketchum, Christian J
Project Start
1981-08-01
Project End
2016-08-31
Budget Start
2012-09-15
Budget End
2013-08-31
Support Year
28
Fiscal Year
2012
Total Cost
$180,027
Indirect Cost
$71,277
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
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 rat proximal tubule and loop of Henle. Am J Physiol Renal Physiol 308:F1076-97
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
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
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
Weinstein, Alan M (2015) A mathematical model of the rat nephron: glucose transport. Am J Physiol Renal Physiol 308:F1098-118
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
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
Wen, Donghai; Cornelius, Ryan J; Rivero-Hernandez, Dianelys et al. (2014) Relation between BK-α/β4-mediated potassium secretion and ENaC-mediated sodium reabsorption. Kidney Int 86:139-45
Wall, Susan M; Weinstein, Alan M (2013) Cortical distal nephron Cl(-) transport in volume homeostasis and blood pressure regulation. Am J Physiol Renal Physiol 305:F427-38

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