Polymerized type I collagen reduces chronic cyclosporine nephrotoxicity

Polymerized type I collagen (P-collagen) has been successfully used to reduce human hypertrophic scars due to its anti-fibrotic and anti-inflammatory properties. We therefore carried out a study to determine if P-collagen reduces functional and structural injury in chronic cyclosporine [cyclosporine A (CsA)] nephropathy.

Four groups of six male Wistar rats fed with a low sodium diet were treated with vehicle, P-collagen (0.8 mg/day, i.p.), CsA (15 mg/kg) or CsA + P-collagen for 15 days. Mean arterial pressure, renal blood flow and glomerular filtration rate were measured in all groups. Structural injury such as arteriolopathy, tubulo-interstitial fibrosis (TI-fibrosis) and positive apoptotic cells were quantified. The mRNA expression levels of transforming growth factor-beta (TGF-beta), kidney injury molecule (Kim-1), alpha-smooth muscle actin (alpha-SMA), glutathione peroxidase, catalase and Cu/Zn superoxide dismutase (SOD) as well as MnSOD were assessed. Antioxidant enzyme activity, renal lipoperoxidation and urinary excretion of oxygen peroxide (UH(2)O(2)V) were determined.

Cyclosporine produced renal dysfunction and induced the development of arteriolopathy, TI-fibrosis and tubular apoptosis. These alterations were associated with increases in TGF-beta, Kim-1 and alpha-SMA mRNA levels as well as with a significant increase of oxidative stress and a reduction of SOD activity. P-Collagen partially ameliorated CsA-induced renal dysfunction and structural injury and prevented both tubular apoptosis and increased oxidative stress. This renoprotective effect was found to be associated with a reduction of TGF-beta, Kim-1 and alpha-SMA mRNA levels.

This study has therefore demonstrated that P-collagen appears to have anti-fibrotic and anti-apoptotic properties and highlights the possibility that the compound might be useful in a strategy to reduce chronic CsA nephrotoxicity.