Pharmacological targeting on this pivotal proinflammatory macrophage subset by two small‐molecule inhibitors of S100a8/a9 signaling, significantly improved renal function and reduced mortality in bilateral IRI (bIRI) murine model, and ameliorated kidney injury and long‐term renal fibrosis in the unilateral IRI (uIRI) murine model. This evidence concerns the gene S100A8 and renal fibrosis.