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.