Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy.
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.
Suganami
Takayoshi
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mukoyama
Masashi
M
Mori
Kiyoshi
K
Yokoi
Hideki
H
Koshikawa
Masao
M
Sawai
Kazutomo
K
Hidaka
Shuji
S
Ebihara
Ken
K
Tanaka
Tomohiro
T
Sugawara
Akira
A
Kawachi
Hiroshi
H
Vinson
Charles
C
Ogawa
Yoshihiro
Y
Nakao
Kazuwa
K
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
D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D020738:Leptin