title: Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy.
abstract: Diabetic nephropathy is the leading cause of end-stage renal disease, for which effective therapy to prevent the progression at advanced stages remains to be established. There is also a long debate whether diabetic glomerular injury is reversible or not. Lipoatrophic diabetes, a syndrome caused by paucity of adipose tissue, is characterized by severe insulin resistance, dyslipidemia, and fatty liver. Here, we show that a genetic model of lipoatrophic diabetes (A-ZIP/F-1 mice) manifests a typical renal injury observed in human diabetic nephropathy that is associated with glomerular hypertrophy, diffuse and pronounced mesangial widening, accumulation of extracellular matrix proteins, podocyte damage, and overt proteinuria. By crossing A-ZIP/F-1 mice with transgenic mice overexpressing an adipocyte-derived hormone leptin, we also reveal that leptin completely prevents the development of hyperglycemia and nephropathy in A-ZIP/F-1 mice. Furthermore, continuous leptin administration to A-ZIP/F-1 mice by minipump beginning at 40 weeks of age significantly alleviates the glomerular injury and proteinuria. These findings demonstrate the therapeutic usefulness of leptin at least for a certain type of diabetic nephropathy. The model presented here will serve as a novel tool to analyze the molecular mechanism underlying not only the progression but also the regression of diabetic nephropathy.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
authors.forename: Masao
authors.initials: M
authors.lastname: Koshikawa
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Sawai
authors.forename: Shuji
authors.initials: S
authors.lastname: Hidaka
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Charles
authors.initials: C
authors.lastname: Vinson
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003928:Diabetic Nephropathies / Q000150:complications*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D007674:Kidney Diseases / Q000097:blood / Q000473:pathology / Q000517:prevention & control* / Q000652:urine; D007678:Kidney Glomerulus / Q000166:cytology; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D019076:Transgenes / Q000235:genetics
chemical_list: D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D020738:Leptin