Integrin α 1 β 1 Promotes Interstitial Fibrosis and Cyst Growth in a Mouse Model of Polycystic Kidney Disease.

Abstract

KEY POINTS: Multiomic analysis of the Pkd1nl/nl mouse and human autosomal dominant polycystic kidney disease tissue identified upregulation of integrin- α 1. Global knockout of integrin subunit α 1 reduced kidney cyst size and preserved kidney function. Loss of integrin- α 1 in Pkd1nl/nl mice precluded interstitial fibrosis, which we suggest was due to reduced fibroblast cell proliferation. BACKGROUND: Cystogenesis and interstitial fibrosis are contributing factors to kidney failure in individuals with autosomal dominant polycystic kidney disease (ADPKD). The molecular and cellular mechanisms involved in cyst growth and fibrosis are complex, and new therapies are urgently needed to improve clinical outcomes. METHODS: We used mass spectrometry-based proteomics to identify molecular changes in the Pkd1nl/nl mouse model of ADPKD and selected integrin- α 1 as a candidate of interest to follow-up in functional studies. Mice lacking integrin- α 1 ( Itga1-/- ) were crossed to Pkd1nl/nl mice, and effects on kidney function and kidney histology were measured. We investigated the effects of integrin- α 1 depletion on fibrosis markers using quantitative RT-PCR, Western blot, and immunofluorescence. RESULTS: Proteomic analysis of the Pkd1nl/nl mouse showed increased abundance of integrin- α 1. 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 Pkd1nl/nlItga1-/- mouse. We observed a significant reduction in kidney volume and kidney dysfunction in Pkd1nl/nl mice lacking integrin- α 1. Kidneys from Pkd1nl/nlItga1-/- mice had smaller cysts, reduced interstitial expansion, and less tubular atrophy. The myofibroblast marker α -smooth muscle actin remained switched on in Pdgfrb + stromal cells of Pkd1nl/nlItga1-/- kidneys, suggesting that integrin- α 1 is not needed for activation of fibroblasts. Analysis of cell proliferation markers suggested that integrin- α 1 promoted fibroblast expansion in response to cystic injury. CONCLUSIONS: These results highlight a previously unrecognized role for integrin- α 1 in cyst growth and fibrosis in PKD.