Kidney Week

Abstract: FR-OR10

Integrin α1β1 Regulates Myofibroblast Expansion in Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  October 25, 2024 | Location: Room 23, Convention Center
  Abstract Time: 04:30 PM - 04:40 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Naylor, Richard William, The University of Manchester, Manchester, United Kingdom

Richard William Naylor, PhD

• Grenier, Celine, The University of Manchester, Manchester, United Kingdom

Celine Grenier, PhD

• Peters, Dorien J.M., Universiteit Leiden, Leiden, Netherlands

Dorien J.M. Peters, PhD

• Pozzi, Ambra, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ambra Pozzi, PhD, DrPH

• Lennon, Rachel, The University of Manchester, Manchester, United Kingdom

Rachel Lennon, MBBS, PhD

Group or Team Name

• Naylor Lab.

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common, potentially lethal disease, affecting 1 in 1000 individuals. A major issue preventing effective treatment is the lack of anti-fibrotic therapies to preclude the interstitial fibrosis that ultimately causes kidney failure in patients with ADPKD and other chronic kidney diseases.

Methods

Mass spectrometry (MS)-based proteomics were used to determine how extracellular matrix (ECM) protein composition changes in whole kidneys taken from a hypomorphic mouse model of ADPKD (Pkd1^nl/nl) and littermate controls. Postnatal day 1 (P1) and P28 were used to determine temporal changes in the proteome. scRNA-seq and immunofluorescence on mouse and human tissue was used to further investigate integrin α1.

Results

Proteomic and histological analysis at P1 showed no fibrosis, but by P28 extensive ECM deposition was observed along with other markers of fibrosis (Acta2, Lcn2, Serpine1, Postn). We found integrin α1 to be up-regulated, along with other cell-matrix receptors. Integrin α1 has previously been shown to regulate cell proliferation in dermal fibroblasts and regulate collagen deposition in the glomerulus. However, a role for integrin α1 in PKD has not previously been investigated. In human healthy and ADPKD kidney biopsies, integrin α1 expression was observed in the interstitial mesenchyme. scRNA-seq data confirmed integrin α1 is expressed in fibroblasts and myofibroblasts. To determine a functional role for integrin α1 in PKD, we created Pkd1^nl/nlItga1^-/- mice. These mice had reduced kidney weight, kidney dysfunction (BUN/uACR), and cyst size when compared to Pkd1^nl/nl mice, suggesting depletion of integrin α1 is protective. Strikingly, interstitial fibrosis was significantly reduced in Pkd1^nl/nlItga1^-/- kidneys. Analysis of αSMA in these mice showed that, whilst myofibroblast transdifferentiation occurred, there were far fewer myofibroblasts present in Pkd1^nl/nlItga1^-/- kidneys. Cell proliferation assays in vivo and in primary fibroblast cultures determined myofibroblast expansion was reduced when integrin α1 is depleted.

Conclusion

Integrin α1 is a regulator of cell proliferation in kidney fibroblasts. Given its depletion is non-lethal, integrin α1 is likely to be and is a promising future target for anti-fibrotic therapies for kidney diseases involving interstitial fibrosis.