title: Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice.
abstract: OBJECTIVE
  Sodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect.
  
  
  METHODS
  We induced diabetes using a low dose streptozotocin protocol in 7-8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice).
  
  
  RESULTS
  Diabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.
  
  
  CONCLUSIONS
  Hence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Muralikrishna
authors.initials: M
authors.lastname: Gangadharan Komala
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Gross
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Harshini
authors.initials: H
authors.lastname: Mudaliar
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Chunling
authors.initials: C
authors.lastname: Huang
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Pegg
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mather
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Shen
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: Renal Research Lab, Kolling Institute of Medical Research, Sydney University, Royal North Shore Hospital, St Leonards, Australia.
authors.forename: Usha
authors.initials: U
authors.lastname: Panchapakesan
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013311:Streptozocin / Q000633:toxicity; D000077333:Telmisartan; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D001562:Benzimidazoles; D001565:Benzoates; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005353:Fibronectins; D051272:Glucose Transporter Type 1; D005960:Glucosides; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D051195:Toll-Like Receptor 2; D053773:Transforming Growth Factor beta1; D013311:Streptozocin; D052250:Nitric Oxide Synthase Type III; C570240:empagliflozin; D000077333:Telmisartan