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C-Peptide Signals via G_i to Protect against TNF-–Mediated Apoptosis of Opossum Kidney Proximal Tubular Cells

Nawal M. Al-Rasheed^*, Gary B. Willars^* and Nigel J. Brunskill^,

^* Department of Cell Physiology and Pharmacology; Department of Infection, Immunity and Inflammation, University of Leicester School of Medicine; and Department of Nephrology, Leicester General Hospital, Leicester, United Kingdom

Address correspondence to: Dr. Nigel J Brunskill, Department of Nephrology, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. Phone: +44-116-258-8043; Fax: +44-116-258-4764; E-mail: njb18{at}le.ac.uk

Received for publication August 1, 2005. Accepted for publication January 10, 2006.

Cell loss by apoptosis occurs in renal injury such as diabetic nephropathy. TNF- is a cytokine that induces apoptosis and has been implicated in the pathogenesis of diabetic nephropathy. The aim was to investigate whether C-peptide or insulin could modulate TNF-–mediated cell death in opossum kidney proximal tubular cells and to examine the mechanism(s) of any effects observed. C-peptide and insulin protect against TNF-–induced proximal tubular cell toxicity and apoptosis. Cell viability was analyzed by methylthiazoletetrazolium assay; cell viability was reduced to 60.8 ± 2.7% of control after stimulation with 300 ng/ml TNF-. Compromised cell viability was reversed by pretreatment with 5 nM C-peptide or 100 nM insulin. TNF-–induced apoptosis was detected by DNA nick-end labeling and by measuring histone associated DNA fragments using ELISA. By ELISA assay, 300 ng/ml TNF- increased apoptosis by 145.8 ± 4.9% compared with controls, whereas 5 nM C-peptide and 100 nM insulin reduced apoptosis to 81.6 ± 4.8 and 77.4 ± 3.1% of control, respectively. The protective effects of C-peptide and insulin were associated with activation of NF-B. Activation of NF-B by C-peptide was pertussis toxin sensitive and dependent on activation of G_i. Phosphatidylinositol 3-kinase but not extracellular signal regulated mitogen-activated protein kinase mediated C-peptide and insulin activation of NF-B. The cytoprotective effects of both C-peptide and insulin were related to increased expression of TNF receptor–associated factor 2, the product of an NF-B–dependent survival gene. These data suggest that C-peptide and/or insulin activation of NF-B–regulated survival genes protects against TNF-–induced renal tubular injury in diabetes. The data further support the concept of C-peptide as a peptide hormone in its own right and suggest a potential therapeutic role for C-peptide.

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