Researchers highlight the impact of macrophage subtypes on acute renal injury to CKD transition

Acute kidney injury (AKI) is a condition in which the kidneys are unable to effectively filter waste from the blood, leading to various health complications. Numerous studies have shown that acute kidney injury (AKI) subsequently leads to long-term kidney damage and progresses to chronic kidney disease (CKD), a more serious form of kidney failure. The transition from AKI to CKD is dependent on several factors, such as sepsis, type of surgery and the presence of cardiovascular disease.

At present, the exact mechanisms underlying this multifactorial transition are unclear. Unraveling these mechanisms may contribute to the development of therapeutic strategies to prevent the AKI-CKD transition. It is currently known that macrophages, a type of immune cell, play a key role in the transition from AKI to CKD.

To further investigate the role of macrophages, a team of researchers led by Dr. Xiaoming Meng of Anhui Medical University in China published a review article highlighting the impact of different macrophage subtypes on the transition from AKI to CKD. This article, which was published in the Chinese medical journalalso examined the potential of macrophage-targeted therapy in the prevention of the AKI-CKD transition.

The source from which a macrophage is derived influences its phenotype and function. In fact, macrophages can evolve into multiple phenotypes, each playing a different role in regulating renal failure and recovery. For example, resident macrophages, which are specific for the renal tissue, are involved in anti-inflammatory processes during renal repair, while circulating macrophages, which are derived from blood monocytes, play a pro-inflammatory role in migrating to the injury site.

In general, macrophages are divided into two types: M1 and M2. A few studies have suggested that M1 macrophages, which are pro-inflammatory, play a role in certain early processes associated with the development of AKI. On the other hand, M2 macrophages have been found to reduce the inflammation and fibrosis associated with AKIs.

How do proinflammatory macrophages contribute to CKD? dr. Meng states: “Kidney damage leading to CKD is enhanced by: pro-inflammatory macrophages. These macrophages accelerate kidney inflammation by releasing various pro-inflammatory cytokines and chemokines or by triggering abnormal wound healing processes, which ultimately lead to renal fibrosis.”

The unique nature of macrophages allows them to change their phenotype from M1 to M2 in response to kidney damage – a process known as polarization. Macrophages can also alter the kidney microenvironment through interactions with endothelial cells, immune cells, fibroblasts, and tubular epithelial cells (TECs). For example, macrophages that infiltrate the kidney in response to injury promote TEC injury and death, ultimately blocking the AKI-CKD transition caused by the TECs.

In sepsis-induced AKI, Csf2, a cytokine secreted by damaged TECs, promotes the transition from M1 macrophages to M2 macrophages. Interestingly, certain M2 macrophages expressing CD206 and/or CD163 receptors contribute to subclinical inflammation, tubular damage and the progression of renal fibrosis – a stark contrast to their usual anti-inflammatory behavior. In addition, under extreme inflammation, M2 macrophages adopt a ‘pro-fibrotic phenotype’, activating myofibroblasts, cells involved in wound contraction and healing.

Unexpectedly, we discovered that macrophages can directly transdifferentiate into myofibroblasts, through a process known as macrophage-myofibroblast transition (MMT). These newly formed myofibroblasts increase renal fibrosis, ultimately leading to renal failureDr. Meng explained. At this time, the exact role of MMT in the AKI-CKD transition is unclear.

The paper also discusses three signaling pathways that contribute to the transition from AKI to CKD, including the Notch signaling pathway, the TGF-β/Smad signaling pathway, and the Wnt/β-catenin signaling pathway. †Targeting the pathways that regulate macrophage and MMT activation or modification of macrophage phenotypes may represent a promising therapeutic approach for renal disease, by blocking the transition from AKI to CKDDr. Meng says, discussing how to prevent the AKI-CKD transition.

Therapeutic strategies that interfere with the activation and pathogenic role of macrophages in this transition have been extensively studied. The article highlights the role of molecules known as clodronate liposomes, which can deplete macrophages and reduce the degree of renal fibrosis. Altering the activation of macrophages and blocking factors with which they interact can also prevent renal fibrosis and subsequent failure.

In addition, treatment with a compound known as quercetin has been shown to block macrophage infiltration and M2 polarization. In addition, a receptor known as colony stimulating factor (CSF)-1 influences the proliferation, differentiation and survival of macrophages. Blocking the gene encoding this receptor can lead to an inhibition of macrophage proliferation in the kidney. In addition, a molecule known as vorapaxar has been reported to suppress macrophages by blocking pathways involved in the transition from AKI to CKD.

The insights from this article will contribute to the development of additional therapeutic strategies against the AKI-CKD transition!

Source:

Reference magazine:

Meng, X., et al. (2022) Directing role of macrophages in the transition from acute kidney injury to chronic kidney disease. Chinese medical journal. doi.org/10.1097/CM90000000000002100

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