title: Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat.
abstract: Tubuloglomerular feedback (TGF) stabilizes nephron function from minute to minute and adapts to different steady-state inputs to maintain this capability. Such adaptation inherently renders TGF less efficient at buffering long-term disturbances, but the magnitude of loss is unknown. We undertook the present study to measure the compromise between TGF and TGF adaptation in transition from acute to chronic decline in proximal reabsorption (Jprox). As a tool, we blocked proximal tubule sodium-glucose cotransport with the SGLT2 blocker dapagliflozin in hyperglycemic rats with early streptozotocin diabetes, a condition in which a large fraction of proximal fluid reabsorption owes to SGLT2. Dapagliflozin acutely reduced proximal reabsorption leading to a 70% increase in early distal chloride, a saturated TGF response, and a major reduction in single nephron glomerular filtration rate (SNGFR). Acute and chronic effects on Jprox were indistinguishable. Adaptations to 10-12 days of dapagiflozin included increased reabsorption by Henle's loop, which caused a partial relaxation in the increased tone exerted by TGF that could be explained without desensitization of TGF. In summary, TGF contributes to long-term fluid and salt balance by mediating a persistent decline in SNGFR as the kidney adapts to a sustained decrease in Jprox.
authors.affiliation: Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, 92161, USA. sthomson@ucsd.edu
authors.forename: Scott C
authors.initials: SC
authors.lastname: Thomson
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
authors.forename: Cynthia
authors.initials: C
authors.lastname: Miracle
authors.forename: Hadi
authors.initials: H
authors.lastname: Mansoury
authors.forename: Jean
authors.initials: J
authors.lastname: Whaley
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Prabhleen
authors.initials: P
authors.lastname: Singh
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D005960:Glucosides / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D013311:Streptozocin