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Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron.

Authors
  • Layton, Anita T1
  • Vallon, Volker2
  • Edwards, Aurélie3
  • 1 Department of Mathematics, Duke University, Durham, North Carolina; [email protected]
  • 2 Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, California, and San Diego Veterans Affairs Healthcare System, San Diego, California; and.
  • 3 Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Université Paris Descartes, Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale UMRS 1138, Centre National de la Recherche Scientifique ERL 8228, Centre de Recherche des Cordeliers, Paris, France. , (France)
Type
Published Article
Journal
AJP Renal Physiology
Publisher
American Physiological Society
Publication Date
Jun 01, 2016
Volume
310
Issue
11
Identifiers
DOI: 10.1152/ajprenal.00543.2015
PMID: 26764207
Source
Medline
Keywords
License
Unknown

Abstract

Diabetes increases the reabsorption of Na(+) (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption [Formula: see text] along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising [Formula: see text] by 5-12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments.

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