title: Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice.
abstract: Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gallo
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Micheal S
authors.initials: MS
authors.lastname: Ward
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Fotheringham
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Aowen
authors.initials: A
authors.lastname: Zhuang
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Borg
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Flemming
authors.affiliation: University of Queensland Biological Resources, St Lucia, Queensland, Australia.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Harvie
authors.affiliation: School of Medicine, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Toni L
authors.initials: TL
authors.lastname: Kinneally
authors.affiliation: Science and Engineering Faculty, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Shang-Ming
authors.initials: SM
authors.lastname: Yeh
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Domenica A
authors.initials: DA
authors.lastname: McCarthy
authors.affiliation: Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Bavaria, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.affiliation: Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Pollock
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
authors.forename: Usha
authors.initials: U
authors.lastname: Panchapakesan
authors.affiliation: Glycation and Diabetes, Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.|Mater Clinical School of Medicine, University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000419:Albuminuria / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005960:Glucosides / Q000008:administration & dosage* / Q000494:pharmacology; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000071068:Lipocalin-2 / Q000652:urine; D008297:Male; D051379:Mice; D016896:Treatment Outcome
chemical_list: D001559:Benzhydryl Compounds; D015415:Biomarkers; D005960:Glucosides; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D007004:Hypoglycemic Agents; C489506:LCN2 protein, human; D000071068:Lipocalin-2; C570240:empagliflozin