Understanding the Anti-inflammatory Effect of C-peptide in Kidney

Patients with diabetes are at high risk of developing long-term complications, including diabetic kidney disease. Recent data suggest that type 1 diabetes might be a dual hormone deficiency disease in which secretion of insulin and C-peptide is insufficient. Insulin supplementation is provided as part of treatment regimes, however, C-peptide depletion remains untreated. In this study, the potential beneficial effect of C-peptide replacement on renal cell signalling and biochemical markers of inflammation was investigated. Using cultured human renal cells (HEK-293A and TERT/1), incubation with 0.3 to 10nM C-peptide resulted in stimulatory effects on the key intracellular signalling pathway to MAP kinase (ERK1/2).

This effect was further investigated in presence of 2.5mM inorganic phosphate (Pi), a plasma Pi concentration that occurs in in rodents but not in healthy humans. Both Pi and C-peptide activated ERK1/2 in TERT/1 cells, and a positive interaction (synergism) was found between the effects of Pi and C-peptide. This response to Pi occurred without detectable change in the intracellular Pi concentration and was mimicked by non-metabolisable Pi analogues orthovanadate, phosphite and hypophosphite, consistent with a recent report of sensing of extracellular Pi by SLC20 transporter proteins (PiT1 and PiT2) in the plasma membrane which then signal to ERK1/2. C-peptide (at a physiologically relevant concentration of 3nM) also decreased mRNA expression of Pi transporters PiT2 and XPR1 and the activity of total Na+-linked Pi influx by 30% in TERT/1 cells, suggesting that C-peptide may contribute to regulation of renal Pi transport.

The proposed renoprotective effect of C-peptide was investigated in vivo. Streptozotocin-induced diabetes in rats resulted in upregulation of transforming growth factor-β and Type IV collagen. Administration of C-peptide prevented diabetes-induced overexpression of TGF-β and Col-IV mRNA, and TGF-β protein in kidney tissue. C-peptide administration also resulted in down-regulation of inflammatory marker proteins; monocyte chemo-attractant protein-1, inter-cellular adhesion molecule-1, vascular cell adhesion molecule-1, vascular endothelial growth factor-A, RANTES, tumour necrosis factor-α and interleukin-1β. Despite the older views that portrayed C-peptide as an inert molecule with no bioactivity, the data presented in this study, add to growing evidence supporting an active role for C-peptide in the diabetic milieu, and suggest that (at least in vitro) the response to C-peptide may be enhanced at the elevated extracellular Pi concentration.