| Title: | Collagen V regulates renal function after kidney injury and can be pharmacologically targeted to enhance kidney repair in mice |
| Journal: | Science Translational Medicine |
| Published: | 9 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40203084/ |
| DOI: | https://doi.org/10.1126/scitranslmed.ads7714 |
Publication 14719
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Kidney fibrosis determines clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar differs from that of healthy kidney extracellular matrix (ECM), but the functional importance of altered collagen types in injured kidneys remains unclear. Using human population studies, we show that circulating protein and renal mRNA amounts of collagen V A1 (COL5A1) exhibited associations with kidney disease and incident CKD risk. We show that Col5a1 regulates the degree of postinjury fibrosis and renal function. Mice with conditionally knocked out Col5a1 (Col5a1 CKO) exhibited decreased renal function and greater renal fibrosis after dietary adenine- or ureteric obstruction-mediated kidney injury. Renal fibroblasts in Col5a1 CKO animals up-regulated the profibrotic αvβ3 integrin. Inhibition of αvβ3 signaling with a small molecule, cilengitide, rescued postinjury renal function in Col5a1 CKO animals. Using the hybrid mouse diversity panel that comprises 100 diverse inbred strains of mice, we observed that gene expression of Col5a1 after injury exhibited genetic variation across 100 strains. Strains with low Col5a1 expression after injury exhibited worse renal function compared with animals that had higher degrees of expression. We next measured Col5a1 expression in peripheral blood mononuclear cells in mice to identify nonresponder strains that did not have increased Col5a1 expression after kidney injury. We observed that administration of cilengitide in nonresponder strains significantly rescued postinjury renal fibrosis and function. These studies point to the feasibility of precision medicine approaches to target Col5a1 for enhancing renal repair.</p>
12 Keywords
- Animals
- Collagen Type V
- Fibroblasts
- Fibrosis
- Humans
- Integrin alphaVbeta3
- Kidney
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Renal Insufficiency, Chronic
18 Authors
- Lianjiu Su
- Qihao Sun
- Yusheng Li
- Juan Felipe Alvarez
- Bo Tao
- Guanglin Zhang
- Yiqian Gu
- Mark R Hanudel
- Alejandro Espinoza
- Linlin Zhang
- Calvin Pan
- James R Hilser
- Jaana A Hartiala
- Shen Li
- Matteo Pellegrini
- Hooman Allayee
- Aldons J Lusis
- Arjun Deb
1 Application
| Application ID | Title |
|---|---|
| 33307 | Sex-specific Genetic Determinants of Cardiometabolic Traits |
Enabling scientific discoveries that improve human health