SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice.
Our previous work has shown that gene knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300 mg/dl) and prevented glomerular hyperfiltration but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300 mg/kg of diet for 15 wk; corresponding to 60-80 mg·kg(-1)·day(-1)) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita diabetes, empagliflozin, and Akita + empagliflozin similarly increased renal membrane SGLT2 expression (by 38-56%) and reduced the expression of SGLT1 (by 33-37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/SGLT1 protein expression are expected to enhance the BG-lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187-237 vs. 517-535 mg/dl in vehicle group; 100-140 mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306 μl/min) and completely prevented the diabetes-induced increase in glomerular filtration rate (GFR) (255 vs. 397 μl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG.
Div. of Nephrology and Hypertension, Depts. of Medicine and Pharmacology, Univ. of California San Diego and Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr. (9151 San Diego, CA 92161. vvallon@ucsd.edu.
Volker
V
Vallon
Maria
M
Gerasimova
Michael A
MA
Rose
Takahiro
T
Masuda
Joseph
J
Satriano
Eric
E
Mayoux
Hermann
H
Koepsell
Scott C
SC
Thomson
Timo
T
Rieg
D017667:Adipocytes / Q000187:drug effects / Q000648:ultrastructure; D000419:Albuminuria / Q000188:drug therapy*; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000517:prevention & control*; D004326:Drinking / Q000502:physiology; D004435:Eating / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005960:Glucosides / Q000494:pharmacology*; D006339:Heart Rate / Q000502:physiology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D007678:Kidney Glomerulus / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D060888:Real-Time Polymerase Chain Reaction; D051269:Sodium-Glucose Transporter 1 / Q000096:biosynthesis / Q000235:genetics; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001559:Benzhydryl Compounds; D015415:Biomarkers; D001786:Blood Glucose; D005960:Glucosides; C495675:Slc5a1 protein, mouse; C490299:Slc5a2 protein, mouse; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin
diabetes; diabetic nephropathy; gluconeogenesis; inflammation; phosphoenolpyruvate carboxykinase; proximal tubule; renal growth