TSC1 Affects the Process of Renal Ischemia-Reperfusion Injury by Controlling Macrophage Polarization

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.

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

“…The MAPK/NF-κB/STAT pathway plays a crucial role in macrophages, which can be affected by a variety of factors to change their phenotype and, thus, affect their function [ 15 , 16 , 19 , 33 ]. In line with previous reports [ 34 , 35 , 36 ], LPS + IFN-γ treatment significantly resulted in phosphorylation of ERK, p38, JNK, p50 and p65 ( Figure 6 A,C), and IL-4 treatment led to phosphorylation of Akt, STAT3 and STAT6 in THP-1 ( Figure 7 A), demonstrating the activation of the MAPK-NF-κB pathway or the Akt/STAT pathway in M1 or M2 macrophage polarization, respectively. However, in the presence of rTcpC (LPS + IFN-γ + rTcpC group), the LPS + IFN-γ-induced phosphorylation of ERK, p38, p50 and p65, but not JNK, was profoundly attenuated ( Figure 6 A,C).…”

Urine Macrophages Polarization Predicts Renal Function Recovery after Nephron-Sparing Surgery in Patients with Renal Cell Carcinoma

“…In contrast, M2 macrophages had an anti-inflammatory response and ameliorated ischemic/reperfusion (I/R). Similar phenomena were observed in RIRI and myocardial IRI [16,[26][27][28], indicating macrophages polarization was closely associated with the severity of I/R and might be used as a potential biomarker of postoperative renal function recovery.…”

Identification of Subtypes and a Delayed Graft Function Predictive Signature Based on Ferroptosis in Renal Ischemia-Reperfusion Injury

“…Mice were anesthetized with an intraperitoneal injection of pentobarbital sodium (60 mg/kg), and the core body temperature was maintained between 34 and 36°C on a heating blanket. According to our previously reported method ( Hu et al, 2021 ), a midline abdominal incision was taken, bilateral renal pedicles were blocked with non-traumatic vascular clips (FT222T, B.BRAUN, Germany) for 30 min, and then the clips were released to allow renal reperfusion for 24 h. The sham-operated mice only exposed bilateral renal pedicles without clamping. The mice were euthanized 24 h after surgery, and kidney tissues were harvested.…”