Abstract
Renal ischemia-reperfusion injury (IRI) contributes to acute kidney injury (AKI), increases morbidity and mortality, and is a significant risk factor for chronic kidney disease (CKD). Macrophage infiltration is a common feature after renal IRI, and infiltrating macrophages can be polarized into the following two distinct types: M1 macrophages, i.e., classically activated macrophages, which can not only inhibit infection but also accelerate renal injury, and M2 macrophages, i.e., alternatively activated macrophages, which have a repair phenotype that can promote wound healing and subsequent fibrosis. The role of TSC1, which is a negative regulator of mTOR signaling that regulates macrophage polarization in inflammation-linked diseases, has been well documented, but whether TSC1 contributes to macrophage polarization in the process of IRI is still unknown. Here, by using a mouse model of renal ischemia-reperfusion, we found that myeloid cell-specific TSC1 knockout mice (termed Lyz-TSC1 cKO mice) had higher serum creatinine levels, more severe histological damage, and greater proinflammatory cytokine production than wild-type (WT) mice during the early phase after renal ischemia-reperfusion. Furthermore, the Lyz-TSC1 cKO mice showed attenuated renal fibrosis during the repair phase of IRI with decreased levels of M2 markers on macrophages in the operated kidneys, which was further confirmed in a cell model of hypoxia-reoxygenation (H/R) in vitro. Mechanistically, by using RNA sequencing of sorted renal macrophages, we found that the expression of most M1-related genes was upregulated in the Lyz-TSC1 cKO group (Supplemental Table 1) during the early phase. However, C/EBPβ and CD206 expression was decreased during the repair phase compared to in the WT group. Overall, our findings demonstrate that the expression of TSC1 in macrophages contributes to the whole process of IRI but serves as an inflammation suppressor during the early phase and a fibrosis promoter during the repair phase.
Highlights
Renal ischemia-reperfusion injury is a major risk factor affecting the prognosis of acute kidney injury (AKI) and the functional recovery and long-term survival of grafts after renal transplantation [1]
Kidney injury molecule-1 (Kim-1) is an acute kidney injury (AKI) biomarker that is always upregulated during the early phase of ischemia-reperfusion injury (IRI)
We found that during the early phase after renal ischemia-reperfusion, the elevated injury in the Lyz-TSC1 cKO mice was related to increased M1 polarization of TSC1 cKO renal macrophages
Summary
Renal ischemia-reperfusion injury is a major risk factor affecting the prognosis of AKI and the functional recovery and long-term survival of grafts after renal transplantation [1]. Macrophages, which are primary components of the phagocytic system, aggravate damage during the initial stage of reperfusion but promote tubular repair and long-term renal fibrosis during the late stage after IRI [3]. Some cytokines and growth factors secreted by macrophages, such as TGF-b1, IL-10, and matrix metalloproteinase (MMP), can contribute to fibrosis [10]. It has been confirmed in various disease models that transforming growth factor-b (TGF-b) is a main cause of fibrosis in most forms of chronic kidney disease (CKD) [11]. Barbarin et al reported that IL-10 inhibits the infiltration of inflammatory cells during the early stage of fibrosis but promoted fibrosis during the later stage [13]
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