Influence of C-peptide on early glomerular changes in diabetic mice.
BACKGROUND
C-peptide has been shown to ameliorate diabetes-induced functional and structural renal changes in animal models as well as in patients with type 1 diabetes. This study aims to examine the molecular effects of C-peptide on early glomerular changes in a mouse model of type 1 diabetes.


METHODS
Fourteen days after induction of diabetes by streptozotocin (STZ), the animals received rat C-peptide for either 24 h or 7 days. Urinary albumin excretion was measured by ELISA. Glomerular mRNA expression of the transforming growth factor (TGF)-beta(1) and type IV collagen was quantified by real-time PCR. The effect of C-peptide on type IV collagen gene expression in cultured murine podocytes was also examined.


RESULTS
C-peptide decreased urinary albumin excretion from 0.29 to 0.18 microg/min (-40.7%, P < 0.01). The transcript level of (alpha3)IV collagen in glomeruli was up-regulated 2.2-fold in diabetic mice and was inhibited by 45-70% (P < 0.05) upon C-peptide treatment. C-peptide suppressed glomerular expression of TGF-beta(1) by 36.6% after 7 days (P < 0.05) but not 24 h after injection. In vitro studies using cultured podocytes revealed that C-peptide dose-dependently inhibited TGF-beta-induced up-regulation of type IV collagen. Moreover, both pertussis toxin (PTX) and a specific inhibitor for extracellular signal-regulated kinase (ERK) pathway reversed the inhibitory effect of C-peptide on TGF-beta. Finally, C-peptide was shown to up-regulate the activity of ERK in podocytes.


CONCLUSIONS
These findings indicate that C-peptide suppresses specific aspects of early glomerular changes in a mouse model of diabetes and that the effect is at least in part mediated via interaction with the TGF-beta signal in glomerular podocytes.
Maezawa
Yoshiro
Y
Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan.
Yokote
Koutaro
K
Sonezaki
Kiriko
K
Fujimoto
Masaki
M
Kobayashi
Kazuki
K
Kawamura
Harukiyo
H
Tokuyama
Takahiko
T
Takemoto
Minoru
M
Ueda
Shiro
S
Kuwaki
Tomoyuki
T
Mori
Seijiro
S
Wahren
John
J
Saito
Yasushi
Y
D000419:Albuminuria; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002096:C-Peptide / Q000494:pharmacology*; D024141:Collagen Type IV / Q000652:urine; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D005786:Gene Expression Regulation; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology*; D051379:Mice; D037342:Pertussis Toxin / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology
D002096:C-Peptide; D024141:Collagen Type IV; D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D037342:Pertussis Toxin; D011494:Protein Kinases