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

ABSTRACT: Kidney fibrosis is a major hallmark of chronic kidney disease and is defined by an excessive accumulation of extracellular matrix, primarily collagens. While collagen synthesis has been extensively investigated, the contribution of impaired collagen degradation to the development of fibrosis remains poorly understood. Collagen degradation involves the activity of proteases producing collagen-derived peptides (CDPs). Here we tested the hypothesis whether reduced collagen degradation participates to the development of kidney fibrosis. For that, CDPs were quantified in pelvic urine of kidney undergoing fibrosis following unilateral ureteral obstruction (UUO). C57Bl6 male mice underwent UUO- or sham-surgery and were sacrificed after 3- or 7-days (3D or 7D). Fibrosis was evaluated by histology. Urinary CDP composition (qualitative-sequences and quantitative-abundances) was analysed by mass spectrometry (MS). Based on collagen protein deposition, UUO-induced fibrosis was detected at 7D and not at 3D. At both 3D and 7D, of the more than 300 significantly different CDPs were found in UUO-pelvic urine, 70% of them displaying a reduced abundance in UUO compared to sham-bladder. In UUO-bladder urine, significant CDPs were found only at 7D with 79% of them displaying increased abundance. CDPs derived from Col1a1, Col1a2 and Col3a1 were the most represented and distributed in clusters along their parental protein sequence. Most clusters were composed of seemingly decreasing length CDPs containing the entire sequence of the shortest CDP. Within the clusters, inter-CDP correlations of abundance were very different between UUO-pelvis and UUO-bladder at 3D and 7D post-UUO. In conclusion, using a mouse model of fibrosis that enables the specific study of CDPs from the fibrotic kidney, we observe that reduced collagen degradation could play a key role in the early stages of fibrosis development. Our research suggests a potential need for a shift in the development of anti-fibrotic strategies, emphasizing not only the inhibition of collagen synthesis but also the enhancement of its degradation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Urine

DISEASE(S): Ureteral Obstruction,Chronic Kidney Disease

SUBMITTER: Carine Froment  

LAB HEAD: Joost Schanstra

PROVIDER: PXD064569 | Pride | 2026-01-12

REPOSITORIES: Pride