Growth hormone receptor antagonism prevents early renal changes in nonobese diabetic mice.
The growth hormone (GH)/insulin-like growth factor (IGF) axis is involved in diabetic renal disease. The role of a specific GH receptor (GHR) antagonist in the development of early renal changes in nonobese diabetic (NOD) mice was investigated. Female diabetic (nonketotic) NOD mice treated with a polyethylene glycol-treated GHR antagonist (2 mg/kg, every other day) (DA group) or saline (D group) and their nonhyperglycemic age-matched littermates (control animals) were euthanized 3 wk after the onset of diabetes. Body weights at euthanasia were similar among the groups. Serum GH levels were markedly elevated, and serum IGF-I levels were significantly decreased in D and DA animals, compared with controls. The increases in kidney weights and glomerular volumes observed for the D group were absent in the DA group. Albuminuria was increased in the D group but was normalized in the DA group. Extractable renal IGF-I protein levels were increased in the D group but were partially normalized in the DA group. Renal IGF-binding protein 1 mRNA levels were increased in the D group but returned to almost normal levels in the DA animals. Kidney IGF-I and GHR mRNA levels were decreased in both the D and DA groups. Renal GH-binding protein mRNA levels remained unchanged in both diabetic groups. GHR antagonism had a blunting effect on renal/glomerular hypertrophy and albuminuria in diabetic NOD mice. These salutary effects were associated with concomitant inhibition of increased renal IGF-I protein levels and were obtained without affecting either somatic growth or circulating GH and IGF-I levels. Therefore, modulation of GH effects may have beneficial therapeutic implications in diabetic nephropathy.
Segev
Y
Y
Molecular Endocrinology Laboratory, Soroka Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Landau
D
D
Rasch
R
R
Flyvbjerg
A
A
Phillip
M
M
D000818:Animals; D001835:Body Weight; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005260:Female; D013006:Growth Hormone / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D051379:Mice; D016688:Mice, Inbred NOD; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors* / Q000235:genetics
C119223:G120K-PEG; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone