Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy

Abstract

The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M 2/2 kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-a blockade with etanercept partially prevented renal atrophy in IRAK-M 2/2 mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage-and TNF-a-dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration.

Antithrombin III prevents progression of chronic kidney disease following experimental ischaemic‐reperfusion injury

“…This speculation could be supported as follows: ( i ) it has been well‐known persistent inflammation contributed to the development of CKD following AKI, especially the activation of pro‐inflammatory immune cells and excess release of pro‐inflammatory chemokine or cytokines. In agreement with previous studies 13, 37, sustained M1‐like macrophage recruitment was observed in the kidney of NX‐IRI rats, which was significantly inhibited by ATIII administration; ( ii ) up‐regulation of M1‐like macrophage‐dependent cytokines such as TNFα and iNOS was blunted in ATIII‐administered rats; ( iii ) previous study showed that prolonged up‐regulation of IL‐1β contributed the CKD progression after IRI 38, which was consistent with our results; more importantly, ATIII was also able to decrease IRI‐induced up‐regulation of IL‐1β.…”

Elevated BP after AKI

“…The likelihood that our results are caused by residual confounding is reduced by the multiple experimental studies showing plausible pathophysiologic pathways connecting AKI to subsequent parenchymal renal damage and elevated BP. 4,5,8,9,[33][34][35][36] To enhance internal validity, we did implement several design decisions as detailed above, recognizing that they may affect generalizability. We excluded patients who had prevalent hypertension at baseline.…”

Macrophage Dynamics in AKI to CKD Progression

“…18 When stimulated ex vivo, IRAK-M KO macrophages generated higher amounts of TNF-a and less IL-10 compared with WT macrophages. 18 To test the functional significance of TNF-a in the AKI to CKD transition in IRAK-M KO mice, the authors treated these mice with the TNF-a inhibitor etanercept beginning at day 5 after ischemia. Compared with untreated ischemic IRAK-M KO mice, etanercept partially but significantly reduced the atrophy, F4/80 1 macrophage accumulation, and fibrosis observed during the recovery from IRI-induced AKI.…”