15
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Sodium-glucose cotransporter 2 (SGLT2) inhibitors enhance urinary glucose, Na + and fluid excretion, and lower hyperglycemia in diabetes by targeting Na + and glucose reabsorption along the proximal convoluted tubule. A goal of this study was to predict the effects of SGLT2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease. To that end, we employed computational rat kidney models to explore how SGLT2 inhibition affects renal solute transport and metabolism when nephron populations are normal or reduced. Model simulations suggested that in a nondiabetic rat, acute and chronic SGLT2 inhibition induces glucosuria, diuresis, natriuresis, and kaliuresis. Those effects were stronger with chronic SGLT2 inhibition (due to SGLT1 downregulation) and tempered by nephron loss. In a diabetic rat with normal nephron number, acute SGLT2 inhibition similarly elevated urine fluid, Na +, and K + excretion, whereas the urinary excretory effects of chronic SGLT2 inhibition were attenuated in proportion to its plasma glucose level lowering effect. Nephron loss in a diabetic kidney was predicted to lower the glucosuric and blood glucose-reducing effect of chronic SGLT2 inhibition, but due to the high luminal glucose delivery in the remaining hyperfiltering nephrons, nephron loss enhanced proximal tubular paracellular Na + secretion, thereby augmenting the natriuretic, diuretic, and kaliuretic effects. A proposed shift in oxygen-consuming active transport to the outer medulla, which may simulate systemic hypoxia and enhance erythropoiesis, was also preserved with nephron loss. These effects may contribute to the protective effects of SGLT2 inhibitors on blood pressure and heart failure observed in diabetic patients with chronic kidney diseases.

          Related collections

          Author and article information

          Journal
          Am J Physiol Renal Physiol
          Am. J. Physiol. Renal Physiol
          ajprenal
          Am J Physiol Renal Physiol
          AJPRENAL
          American Journal of Physiology - Renal Physiology
          American Physiological Society (Bethesda, MD )
          1931-857X
          1522-1466
          1 May 2018
          17 January 2018
          1 May 2019
          : 314
          : 5
          : F969-F984
          Affiliations
          [1] 1Department of Mathematics, Duke University , Durham, North Carolina
          [2] 2Departments of Medicine and Pharmacology, University of California San Diego , La Jolla, California
          [3] 3VA San Diego Healthcare System, San Diego, California
          Author notes
          Address for reprint requests and other correspondence: V. Vallon, VA San Diego Healthcare System, 3350 La Jolla Village Drive (9151), San Diego, CA 92161 (e-mail: vvallon@ 123456ucsd.edu ).
          Article
          PMC6031905 PMC6031905 6031905 F-00551-2017 F-00551-2017
          10.1152/ajprenal.00551.2017
          6031905
          29361669
          f344c415-c675-47a5-88a8-5d0beacda6ac
          History
          : 6 November 2017
          : 28 December 2017
          : 10 January 2018
          Funding
          Funded by: National Institutes of Health
          Award ID: DK112042
          Award ID: DK106102
          Award ID: P30DK079337
          Categories
          Research Article
          Newer Therapies for Diabetic Nephropathy and Their Cardiovascular Effects
          Custom metadata
          True

          epithelial transport,SGLT2 inhibitor,glucose,oxygen consumption,remnant kidney,hypoxia,diabetes,sodium-glucose cotransporter

          Comments

          Comment on this article