Diabetes and hypertension are major risk factors for developing chronic kidney diseases (CKD). Despite intense research, the mechanisms that underlie the pathways to renal hypoxia and CKD remain poorly under- stood. That dif?culty may be attributable to the complex interplay among the millions of renal tubules and vessels that forms the basis for the integrative function of the kidney but that remains to be fully characterized. We have previously developed computational models of the rat kidney that represent the complex interactions, and we aim to extend those models and to conduct simulations that will provide insights into the kidney in health and disease. The proposed project includes (I) To develop a detailed and multiscale computational model of integrative rat kidney function, and to use that model to examine key determinants of kidney function and medullary oxygenation. Simulations of functional knockout and nephron loss will be conducted to determine: What are the necessary nephron structures and functions that must be preserved or should be inhibited to maintain or increase oxygen balance in the vulnerable outer medulla, while maintaining overall key kidney functions? (II) To simulate and gain insights into the pathophysiology and therapeutics of renal hypoxia in hypertension and diabetes. Hypertension and diabetes induce unique effects on the tubular system that increases kidney oxygen consumption. Model simulations will be conducted to investigate factors that impact intrarenal oxygen tension (PO2), particularly in the vulnerable outer medulla, including hypertension-induced shift in Na+ transport to the more distal and less ef?cient nephron segments, elevated oxidative stress, diabetes-induced hyper?ltration and tubular hypertrophy and hyper-reabsorption. We will simulate and investigate the effectiveness of current and novel therapeutic treatments and seek to answer questions like: How can one increase Na+ excretion in hypertension while limiting effects on other kidney functions and preserve medullary oxygenation? In diabetes, what is the in?uence of inhibiting Na+-glucose cotransport on renal NaCl transport and O2 requirement? To what extent do pressure reduction maneuvers increase medullary PO2 and protect the kidney? (III) To conduct experimental studies to assess the renal effects of sodium-glucose cotransporter (SGLT) inhibition. Inhibiting glucose reabsorption along the proximal tubule via SGLT2 is a novel approach for lower blood glucose level in diabetes. We will perform experiments on mice to determine: Does SGLT2 inhibition enhance Na+ transport of vulnerable downstream nephron segments and increase outer medullary hypoxia? Is there any bene?t in the additional inhibition of SGLT1 along the late proximal tubule, which limits Na+ glucose reabsorption along that segment, but may further increase thick ascending limb Na+ transport? Does SGLT inhibition facilitate ischemia- reperfusion injury or impair the recovery? At the completion of these studies, we would have gained new insights into the key determinants of kidney function and medullary oxygenation in the normal kidney, and determined their potential relevance in the pathways from hypertension and diabetes to CKD.

Public Health Relevance

Diabetes and hypertension are major risk factors for developing chronic kidney diseases, which are a growing public health concern that affects one in 10 adults in the United States. Despite intense research, the mechanisms that underlie the pathways to chronic kidney diseases remain incompletely understood. This project seeks to use computational modeling techniques and animal experiments to gain new insights into those path- ways, which may lead to better preventive strategies and therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK106102-01A1
Application #
9096558
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Ketchum, Christian J
Project Start
2016-05-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Thomson, Scott C; Vallon, Volker (2018) Renal Effects of Incretin-Based Diabetes Therapies: Pre-clinical Predictions and Clinical Trial Outcomes. Curr Diab Rep 18:28
Wei, Ning; Gumz, Michelle L; Layton, Anita T (2018) Predicted effect of circadian clock modulation of NHE3 of a proximal tubule cell on sodium transport. Am J Physiol Renal Physiol 315:F665-F676
Rieg, Timo; Vallon, Volker (2018) Development of SGLT1 and SGLT2 inhibitors. Diabetologia 61:2079-2086
Leete, Jessica; Gurley, Susan; Layton, Anita (2018) Modeling Sex Differences in the Renin Angiotensin System and the Efficacy of Antihypertensive Therapies. Comput Chem Eng 112:253-264
Layton, Anita T; Edwards, Aurélie; Vallon, Volker (2018) Renal potassium handling in rats with subtotal nephrectomy: modeling and analysis. Am J Physiol Renal Physiol 314:F643-F657
Layton, A T; Vallon, V (2018) Cardiovascular benefits of SGLT2 inhibition in diabetes and chronic kidney diseases. Acta Physiol (Oxf) 222:e13050
Sgouralis, Ioannis; Evans, Roger G; Layton, Anita T (2017) Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat. Math Med Biol 34:313-333
Edwards, Aurélie; Layton, Anita T (2017) Cell Volume Regulation in the Proximal Tubule of Rat Kidney : Proximal Tubule Cell Volume Regulation. Bull Math Biol 79:2512-2533
Layton, Anita T (2017) A new microscope for the kidney: mathematics. Am J Physiol Renal Physiol 312:F671-F672
Chen, Ying; Fry, Brendan C; Layton, Anita T (2017) Modeling glucose metabolism and lactate production in the kidney. Math Biosci 289:116-129

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