Introduction
Prevalence of hyperuricemia has been rising in recent years due to unhealthy dietary patterns and lifestyles (Bakris et al., 2014; Chen-Xu et al., 2019). The kidneys, eliminating two-third uric acid in healthy individuals, are associated with new and progressive chronic kidney disease (CKD). Kidney impairment owing to hyperuricemia is mainly characterized by chronic interstitial nephritis, urate crystals (or stones), and kidney fibrosis(Sato et al., 2019; Wen et al., 2021). By far, as a modifiable metabolite, uric acid is a potential target to alleviate renal damages induced by hyperuricemia. But in the setting of CKD, it’s controversial whether uric acid-lowering is an effective strategy to prevent or delay CKD progression(Oluwo & Scialla, 2021). Studies on exploring therapeutic targets that participate in hyperuricemia-related CKD are of great significance.
Integrin is the largest family of cell adhesion molecules and is involved in kidney development and diseases(Marek et al., 2014; Muller et al., 1997). Renal fibrosis could be induced by integrins through cell-matrix or cell-cell interactions (Pozzi & Zent, 2013). Integrins are αβ heterodimeric transmembrane glycoproteins and mainly divided into integrin β1, β2, and β3 families according to β subunits(Takada et al., 2007). As transmembrane receptors, integrins participates in cell proliferation, survival and migration, differentiation, and matrix homeostasis(Pozzi & Zent, 2013). Due to lack of enzymatic activity, integrins need to bind adaptor proteins for intracellular signal propagation, such as focal adhesion kinase (FAK), a key tyrosine kinase of intracellular signaling binding to a number of downstream molecules(Guan, 1997).
αMβ2, also known as macrophage antigen 1 (Mac-1), is the predominant leukocyte-specific β2 integrin abundantly expressed in monocytes/macrophages and dendritic cells(Martinez et al., 2020). The αMI-domain within αMβ2 mediates ligand binding and is responsible for substrate specificity, thus integrin αM mainly determined diverse functions of Mac-1(Podolnikova et al., 2015). Previous studies reported that integrin αM (ITGAM) overexpression was associated with macrophage infiltration and renal fibrosis(Dehnadi et al., 2017; Lange-Sperandio et al., 2006). Macrophages accumulate in injured kidneys and present as polarized M1 or M2 phenotype for pro-inflammatory or pro-fibrotic functions, respectively(Lee et al., 2020; Murray, 2017). Macrophage alternative (M2) polarization is considered as an essential feature of fibrosis(Feng et al., 2018). However, it’s not well-elucidated whether ITGAM regulated macrophage M2 polarization in renal fibrosis and signaling pathways involved.
Here, integrin ITGAM is reported as the hub gene promoting macrophage M2 polarization in hyperuricemia-related CKD. We adopted integrated bioinformatic analysis and verified that ITGAM participated in kidney disease development through FAK/Akt1/β-catenin pathway. Our study reveals a mechanism in hyperuricemia-related kidney fibrosis that involves ITGAM expression and signaling related, and provides potential therapeutic targets to prevent or delay the progression of CKD.