Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule.
Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubulesviasodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopicex vitroautoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably,in vivoimaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.
Departments of *Physiology and.
Chiara
C
Ghezzi
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and.
Amy S
AS
Yu
Departments of *Physiology and.
Bruce A
BA
Hirayama
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and.
Vladimir
V
Kepe
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and.
Jie
J
Liu
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and.
Claudio
C
Scafoglio
Lexicon Pharmaceuticals Inc., Woodlands, Texas.
David R
DR
Powell
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and.
Sung-Cheng
SC
Huang
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and.
Nagichettiar
N
Satyamurthy
Molecular and Medical Pharmacology, David Geffen School of Medicine at Univeristy of California Los Angeles, Los Angeles, California; and jbarrio@mednet.ucla.edu CGhezzi@mednet.ucla.edu.
Jorge R
JR
Barrio
Departments of *Physiology and jbarrio@mednet.ucla.edu CGhezzi@mednet.ucla.edu.
Ernest M
EM
Wright
D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism*; D005260:Female; D005960:Glucosides / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*
D001559:Benzhydryl Compounds; D005960:Glucosides; D051297:Sodium-Glucose Transporter 2; C529054:dapagliflozin
Dapagliflozin; SGLT2; diabetes mellitus; microPET