Collagen-Derived Peptides in CKD: A Link to Fibrosis

Abstract

Collagen is a major component of the extracellular matrix (ECM) and has an imminent role in fibrosis, in, among others, chronic kidney disease (CKD). Collagen alpha-1(I) (col1a1) is the most abundant collagen type and has previously been underlined for its contribution to the disease phenotype. Here, we examined 5000 urinary peptidomic datasets randomly selected from healthy participants or patients with CKD to identify urinary col1a1 fragments and study their abundance, position in the main protein, as well as their correlation with renal function. We identified 707 col1a1 peptides that differed in their amino acid sequence and/or post-translational modifications (hydroxyprolines). Well-correlated peptides with the same amino acid sequence, but a different number of hydroxyprolines, were combined into a final list of 503 peptides. These 503 col1a1 peptides covered 69% of the full col1a1 sequence. Sixty-three col1a1 peptides were significantly and highly positively associated (rho > +0.3) with the estimated glomerular filtration rate (eGFR), while only six peptides showed a significant and strong, negative association (rho < −0.3). A similar tendency was observed for col1a1 peptides associated with ageing, where the abundance of most col1a1 peptides decreased with increasing age. Collectively the results show a strong association between collagen peptides and loss of kidney function and suggest that fibrosis, potentially also of other organs, may be the main consequence of an attenuation of collagen degradation, and not increased synthesis.

Urinary Proteomic Signature of Mineralocorticoid Receptor Antagonism by Spironolactone: Evidence from the Randomized-Controlled HOMAGE and PRIORITY Trials

“…28 A recent study examined 5000 UPP datasets randomly selected from healthy participants and patients with CKD. 9 Well-correlated peptides with the same amino-acid sequence, but a different number of hydroxyprolines, were combined into a final list of 503 peptides, which covered 69% of the full COL1A1 sequence. Sixty-three COL1A1 fragments (12.5%) were positively correlated (r > 0.30) with eGFR, suggesting that dysfunction of the kidney, and potentially of other organs, might be due to an attenuation of collagen degradation.…”

“…Sixty-three COL1A1 fragments (12.5%) were positively correlated (r > 0.30) with eGFR, suggesting that dysfunction of the kidney, and potentially of other organs, might be due to an attenuation of collagen degradation. 9 However, studies which reported a decrease in urinary peptide fragments derived from COL1A1 as the hallmark of fibrosis, [7][8][9] had an observational design. Such studies do not allow to draw conclusions about active intervention with MRAs, such as in the context of randomized clinical trials of spironolactone.…”

“…6 In uncontrolled observational studies, a decrease in urinary peptide fragments derived from type-1 collagen characterizes fibrosis. [7][8][9] Given the renewed interest in MRAs, 10,11 the current study investigated whether in a subset of the HOMAGE study population, UPP analysis provided novel information on the influence of MRA by spironolactone on the turnover of collagen I. To seek confirmation of the HOMAGE UPP findings, the UPP of patients at high risk of diabetic nephropathy enrolled in the double-blind placebo-controlled PRIORITY trial 12 was also analyzed.…”

Glycosylation Analysis of Urinary Peptidome Highlights IGF2 Glycopeptides in Association with CKD

“…For the association of the identified glycopeptides with Age, eGFR and Albuminuria, anonymized CE-MS urinary peptide profiles from the Human Urinary Proteome database [ 21 , 30 , 31 ] were considered. These peptide datasets generated in previous studies [ 55 , 56 , 57 , 58 , 59 , 60 , 61 ] were selected based on availability of information on their diagnosis (control or CKD etiology), Age, eGFR and Albuminuria values. The distribution of disease etiology for the retrieved 3810 datasets is presented in Table 4 .…”

Molecular Characteristics and Promoter Analysis of Porcine COL1A1

“…COL1A1 encodes the type I collagen α1 chain, which is associated with cell proliferation, invasion [ 10 , 11 ], and fibrosis [ 12 , 13 , 14 ]. It is also associated with vascular diseases [ 15 ], skeletal injury dysplasia [ 16 ], osteogenesis imperfecta [ 17 ], osteoporosis [ 18 ], and other pathological conditions [ 19 ].…”