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Influence of C‐peptide on early glomerular changes in diabetic mice
Author(s) -
Maezawa Yoshiro,
Yokote Koutaro,
Sonezaki Kiriko,
Fujimoto Masaki,
Kobayashi Kazuki,
Kawamura Harukiyo,
Tokuyama Takahiko,
Takemoto Minoru,
Ueda Shiro,
Kuwaki Tomoyuki,
Mori Seijiro,
Wahren John,
Saito Yasushi
Publication year - 2006
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.612
Subject(s) - medicine , endocrinology , peptide , streptozotocin , transforming growth factor , mapk/erk pathway , chemistry , diabetes mellitus , in vitro , biology , signal transduction , biochemistry
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)‐β 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 µg/min (−40.7%, P < 0.01). The transcript level of (α3)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‐β 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‐β‐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‐β. 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‐β signal in glomerular podocytes. Copyright © 2006 John Wiley & Sons, Ltd.