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Updated: Jun 8, 2025
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Integrin alpha1 beta1 promotes interstitial fibrosis in a mouse model of polycystic kidney disease
C Grenier1, I-H Lin2, Djm Peters3
1Manchester Cell-Matrix Centre, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom.
Abstract:
Fibrosis is the cause of end-stage kidney failure in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). The molecular and cellular mechanisms involved in fibrosis are complex and anti-fibrotic therapies have so far failed to make an impact on patient welfare. Using unbiased proteomics analysis on the Pkd1 nl/nl mouse, we found that expression of the integrin α1 subunit is increased in this model of ADPKD. In human ADPKD tissue and two single cell RNA kidney disease datasets, ITGA1 was also upregulated. To investigate the functional role of this integrin subunit in ADPKD, we generated a Pkd1 nl/nl Itga1 -/- mouse. We observed a significant reduction in kidney volume and kidney dysfunction in mice lacking the integrin α1 subunit. Kidneys from Pkd1 nl/nl Itga1 -/- mice had smaller cysts and reduced interstitial expansion and tubular atrophy. Picrosirius red staining identified a restriction in collagen staining in the interstitium and the myofibroblast marker α smooth muscle actin was also downregulated. Myofibroblast cell proliferation was reduced in Pkd1 nl/nl Itga1 -/- mice and primary fibroblast cultures demonstrated an abrogated fibrogenic phenotype in integrin α1-depleted fibroblasts. These results highlight a previously unrecognised role for the integrin α1 subunit in kidney fibrosis.
Insights
Integrin alpha1 (ITGA1) is upregulated in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and drives kidney fibrosis. Targeting ITGA1 reduced cyst size and kidney dysfunction in ADPKD models.
Area of Science:
- Nephrology
- Molecular Biology
- Integrin Biology
Background:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end-stage kidney failure primarily due to fibrosis.
- Current anti-fibrotic therapies have shown limited success in improving patient outcomes.
- The molecular mechanisms underlying fibrosis in ADPKD are not fully understood.
Purpose of the Study:
- To investigate the role of integrin alpha1 (ITGA1) in the pathogenesis of kidney fibrosis in ADPKD.
- To determine if targeting ITGA1 could be a potential therapeutic strategy for ADPKD.
Main Methods:
- Proteomics analysis of the Pkd1 nl/nl mouse model of ADPKD.
- Analysis of human ADPKD tissue and single-cell RNA sequencing datasets.
- Generation and characterization of Pkd1 nl/nl Itga1 -/- mice.
- Histological analysis including Picrosirius red staining and alpha smooth muscle actin (α-SMA) staining.
- Assessment of myofibroblast proliferation and fibrogenic phenotype in primary fibroblast cultures.
Main Results:
- Integrin alpha1 subunit expression was significantly increased in ADPKD models and human ADPKD kidney tissue.
- Mice lacking integrin alpha1 (Pkd1 nl/nl Itga1 -/-) exhibited reduced kidney volume and improved kidney function.
- Histological examination revealed smaller cysts, reduced interstitial expansion, and less tubular atrophy in Itga1-deficient ADPKD mice.
- Collagen deposition and α-SMA expression were downregulated, indicating reduced fibrosis.
- Myofibroblast proliferation and the fibrogenic phenotype were abrogated in the absence of integrin alpha1.
Conclusions:
- Integrin alpha1 plays a significant, previously unrecognized role in promoting kidney fibrosis in ADPKD.
- Targeting integrin alpha1 represents a potential novel therapeutic approach to mitigate fibrosis and disease progression in ADPKD.
