Reduced collagen degradation in pelvic urine precedes kidney fibrosis induced by unilateral ureteral obstruction

Collagen degradation involves the activity of proteases that produce collagen-derived peptides (CDPs). We tested the hypothesis that reduced collagen degradation is involved in the development of kidney fibrosis. Urine that accumulated in the pelvis of mouse kidney undergoing fibrosis following unilateral ureteral obstruction (UUO) was collected, and CDPs composition was analysed by mass spectrometry. UUO-induced fibrosis was detected 7 days after UUO surgery, but not after 3 days. After just 3 days of UUO, 300 CDPs exhibited significantly altered abundance, with 70% showing reduced levels compared to the non-fibrotic control. Of the more than 300 significantly different CDPs were found after already 3 days, with 70% of them showing a reduced abundance compared to non-fibrotic control. CDPs derived from Col1a1, Col1a2 and Col3a1 were the most represented and were distributed along their parental protein sequence in clusters composed of seemingly decreasing length CDPs containing the entire sequence of the shortest CDP. Within clusters, inter-CDP abundance correlations in pelvic urine were very different to those in bladder urine. In conclusion, using a mouse model of fibrosis that allows the specific study of CDPs from the fibrotic kidney, we found that reduced collagen degradation is involved in the early stages of fibrosis development. Our research suggests that enhancing collagen degradation might be considered in the development of anti-fibrotic strategies.