title: Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus.
abstract: The Na-glucose cotransporter SGLT2 mediates high-capacity glucose uptake in the early proximal tubule and SGLT2 inhibitors are developed as new antidiabetic drugs. We used gene-targeted Sglt2 knockout (Sglt2(-/-)) mice to elucidate the contribution of SGLT2 to blood glucose control, glomerular hyperfiltration, kidney growth, and markers of renal growth and injury at 5 wk and 4.5 mo after induction of low-dose streptozotocin (STZ) diabetes. The absence of SGLT2 did not affect renal mRNA expression of glucose transporters SGLT1, NaGLT1, GLUT1, or GLUT2 in response to STZ. Application of STZ increased blood glucose levels to a lesser extent in Sglt2(-/-) vs. wild-type (WT) mice (∼300 vs. 470 mg/dl) but increased glucosuria and food and fluid intake to similar levels in both genotypes. Lack of SGLT2 prevented STZ-induced glomerular hyperfiltration but not the increase in kidney weight. Knockout of SGLT2 attenuated the STZ-induced renal accumulation of p62/sequestosome, an indicator of impaired autophagy, but did not attenuate the rise in renal expression of markers of kidney growth (p27 and proliferating cell nuclear antigen), oxidative stress (NADPH oxidases 2 and 4 and heme oxygenase-1), inflammation (interleukin-6 and monocyte chemoattractant protein-1), fibrosis (fibronectin and Sirius red-sensitive tubulointerstitial collagen accumulation), or injury (renal/urinary neutrophil gelatinase-associated lipocalin). SGLT2 deficiency did not induce ascending urinary tract infection in nondiabetic or diabetic mice. The results indicate that SGLT2 is a determinant of hyperglycemia and glomerular hyperfiltration in STZ-induced diabetes mellitus but is not critical for the induction of renal growth and markers of renal injury, inflammation, and fibrosis.
authors.affiliation: Department of Medicine, University of California, San Diego, California 92161, USA. vvallon@ucsd.edu
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Michael
authors.initials: M
authors.lastname: Rose
authors.forename: Maria
authors.initials: M
authors.lastname: Gerasimova
authors.forename: Joseph
authors.initials: J
authors.lastname: Satriano
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Platt
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Robyn
authors.initials: R
authors.lastname: Cunard
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.forename: Scott C
authors.initials: SC
authors.lastname: Thomson
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D005919:Glomerular Filtration Rate; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000254:growth & development* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2