Enhanced M1 and Impaired M2 Macrophage Polarization and Reduced Mitochondrial Biogenesis via Inhibition of AMP Kinase in Chronic Kidney Disease

Abstract

Background: Macrophage polarization plays a pivotal role in the process of inflammation which is common in chronic kidney disease (CKD). Macrophages polarization under the condition of CKD remains poorly understood. Here we tested the hypothesis that CKD promotes macrophage M1 polarization. Methods: A rat model of CKD was established by reduced renal mass (RRM). Polarization of macrophages was induced in ex vivo macrophages from RRM rats and cultured ones under the condition of uremic serum. The markers were evaluated by RT-PCR, western blot, and flow cytometer. Results: Our data showed that macrophages from RRM rats displayed enhanced M1 and impaired M2 polarization as revealed by increased M1 markers (tumor necrosis factor α, IL-6, IL-12p40, nitric oxide) and decreased M2 markers (IL-10, CD206, arginase activity) in response to LPS and IL-4 induction, respectively. Treatment with uremic sera in peritoneal and bone marrow derived macrophages from normal rats led to similar results. Moreover, macrophages from RRM rats and cultured under the condition of uremic sera had reduced mitochondrial biogenesis. The disturbed macrophage polarization and mitochondrial biogenesis were accompanied by reduced activity of adenosine monophosphate-activated protein (AMP)-activated kinase (AMPK). Enhancing activation of AMPK restored mitochondrial biogenesis and M2 macrophage polarization. Conclusion: These observations suggest that CKD disturbs macrophage polarization and mitochondrial biogenesis through inhibition of AMPK. This might provide a novel therapeutic strategy for intervention of chronic inflammation in CKD.

5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis

“…Considering the fact that TLR signalling plays an important role in the pathogenesis of bacterial endophthalmitis and that TLR activation has been implicated in the metabolic reprogramming of DCs and macrophages (Krawczyk et al ., ; Tannahill et al ., ; Cortese et al ., ), further studies are warranted to establish this link in our model. Similarly, several other important topics that need to be addressed include (1) how the metabolic shift occurs in the inflammatory versus the resolution phase of the disease and (2) AMPK activation has been shown to switch the phenotype of monocytes/macrophages from M1 (pro‐inflammatory) to M2 (anti‐inflammatory) (Mounier et al ., ; Li et al ., ), and this macrophage phenotype switching and its role has not been studied in the pathogenesis of bacterial endophthalmitis.…”

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

“…In contrast, M2 macrophages generally contribute to kidney tissue remodeling following AKI by enhancing tubular cell proliferation and repair as well as inducing maladaptive repair of fibrosis 174 . Macrophage infiltration occurs in CKD in both human patients and animal models 175–177 , and notably, the infiltration is followed by M1 macrophage polarization whereas M2 polarization is impaired 177 , predisposing the kidneys to inflammation and tissue damage in AKI.…”

Macrophage metabolism in atherosclerosis

“…Moreover, AMPKα deficiency in macrophages resulted in an increased production of proinflammatory cytokines and a decrease in respiratory capacity and FAO, and a defect in efferocytosis . Interestingly, AMPK and mTOR seem to have antagonistic effects, since activation of AMPK leads to inhibition of mTOR and decreases the proinflammatory profile of M1 macrophages . Conversely, treatment of macrophages with LPS reduces AMPK activity .…”