Macrophages in kidney disease

Abstract

Acute Kidney Injury (AKI) is a well-recognised risk factor for chronic kidney disease (CKD),but the mechanism remains unknown. It is proposed that bone marrow derived macrophages (BMDM) can determine outcome following AKI. However, resident macrophages (MØ) in the kidney are thought to play little part in this. Single Cell RNA Sequencing (scRNA-Seq) was conducted on a mouse model of AKI/CKD (toxin derived through aristolochic acid (AA) injection). A total of 19 myeloid cell clusters were identified including 8 MØ clusters. Resident MØ demonstrated dynamic transcriptomic signatures in response to injury and inflammation. Analysis of these clusters identified Res.MØ.1 that peaked in the recovery state following renal insult, as well as Res.MØ.2 and Res.MØ.3 that peaked in renal fibrosis. Pathway analysis uncovered inflammatory signatures and pathways associated with the fibrotic state. In depth manual analysis of genes expressed by MØ clusters identified dynamic gene expression associated with clusters that peaked in the recovery and non-recovey (fibrosis) state. This analysis identified transcription factor Maf as a possibel mechanistic target. Maf is a transcription factor that is thought to aid MØ maturation and differentiation to an antiinflammatory phenotye. It was expressed most abundantly in Res.MØ.1. Where it was expressed by some other MØ clusters, this was restricted to the recovery disease states. Therefore, a mouse model was developed with specific knock-out of transcription factor Maf in myeloid cells in mice. These mice along with wild-type variants were injected with AA to induce renal fibrosis and demonstrated a higher degree of weight loss than wild-type mice and a higher degree of renal fibrosis, quantified through multiplex immunofluorescence staining. This data has demonstrated that MØ may play an important role in recovery versus nonrecovery following renal insult. It has also indicated that Maf MØ, may play a vital role in the development of renal fibrosis following renal insult