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|Title:||C-Peptide signals via Gαi to protect against TNF-α-mediated apoptosis of opossum kidney proximal tubular cells.|
|Authors:||Al-Rasheed, Nawal M.|
Willars, Gary B.
Brunskill, Nigel J.
|Citation:||Journal of American Society of Nephrology, 2006, 17, pp.986-995|
|Abstract:||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 Gi. 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.|
|Description:||This paper was published as Journal of American Society of Nephrology, 2006, 17, pp.986-995. It is available from http://jasn.asnjournals.org/cgi/content/abstract/17/4/986. Doi: 10.1681/ASN.2005080797|
|Appears in Collections:||Published Articles, Dept. of Cell Physiology and Pharmacology|
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