Acute Kidney Failure (AKI) is a condition in which the kidneys are unable to effectively filter waste products from the blood, leading to various health complications. Numerous studies have shown that acute renal failure (AKI) subsequently leads to long-term kidney damage and progresses to chronic kidney disease (CKD); a more severe form of kidney failure. The transition from ARI to CRI depends on various 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. Currently, it is known that macrophages, which are a type of immune cell, play a key role in the transition from ARI to CRI.
To further explore the role of macrophages, a team of researchers led by Dr. Xiaoming Meng from Anhui Medical University in China, wrote a review article highlighting the impact of different macrophage subtypes on the transition from the IRA to the IRC. This article, published on Chinese medical journalalso explored the potential of macrophage-targeted therapy in preventing AKI-CKD transition.
The source from which a macrophage is derived affects its phenotype and function. In fact, macrophages can evolve into several phenotypes, each playing a different role in the regulation and repair of kidney failure. For example, resident macrophages, specific for renal tissue, are involved in anti-inflammatory processes during renal repair, while circulating macrophages, derived from blood monocytes, play a pro-inflammatory role during migration to the site. of the lesion.
Generally, macrophages are classified into two types: M1 and M2. A few studies have suggested that M1 macrophages, which are pro-inflammatory, play a role in some early processes associated with the development of AKI. On the other hand, M2 macrophages have been shown to reduce inflammation and fibrosis associated with ARIs.
How do pro-inflammatory macrophages contribute to CKD? Dr. Meng says, “Kidney damage that leads to CKD is aggravated by pro-inflammatory macrophages. These macrophages accelerate renal inflammation via the release of several pro-inflammatory cytokines and chemokines or by triggering abnormal healing processes, which eventually lead to renal fibrosis.”
The unique nature of macrophages allows them to change their phenotype from M1 to M2 in response to kidney injury; a process known as polarization. Macrophages can also modify the renal microenvironment through interactions with endothelial cells, immune cells, fibroblasts and tubular epithelial cells (TECs). For example, macrophages infiltrating the kidney in response to injury promote TEC injury and death, which ultimately blocks the TEC-induced AKI-CKD transition.
In sepsis-induced ARF, Csf2, which is a cytokine secreted by injured TECs, promotes the transition from M1 macrophages to M2 macrophages. Interestingly, some M2 macrophages that express CD206 and/or CD163 receptors contribute to subclinical inflammation, tubular damage, and progression of renal fibrosis; a stark contrast to their usual anti-inflammatory behavior. Additionally, in extreme inflammation, M2 macrophages adopt a “pro-fibrotic phenotype” in which they activate myofibroblasts, which are cells involved in wound contraction and healing.
“Unexpectedly, we discovered that macrophages can directly differentiate into myofibroblasts, via a process known as macrophage-myofibroblast transition (MMT). These newly formed myofibroblasts increase kidney fibrosis, which eventually leads to kidney failure.”, said Dr. Meng. At present, the exact role of MMT in the AKI-CKD transition is unclear.
The article also discusses three signaling pathways that contribute to the AKI to CKD transition, including the Notch signaling pathway, the TGF-β/Smad signaling pathway, and the Wnt/β-catenin signaling pathway. “Targeting pathways that regulate macrophage and MMT activation or modification of macrophage phenotypes may be a promising therapeutic approach for kidney disease, by blocking the transition AKI to CKD.”, says Dr. Meng, while explaining how the AKI-CKD transition can be avoided.
Therapeutic strategies that interfere with the activation and pathogenic role of macrophages in this transition have been widely studied. The article highlights the role of molecules known as clodronate liposomes, which can deplete macrophages and reduce the extent of renal fibrosis. Altering the activation of macrophages and the blocking factors with which they interact may also prevent renal fibrosis and subsequent failure.
Additionally, treatment with a compound known as quercetin has been shown to block macrophage infiltration and M2 polarization. Additionally, a receptor known as colony stimulating factor (CSF)-1 influences macrophage proliferation, differentiation, and survival. Blocking the gene that codes for this receptor can lead to inhibition of macrophage proliferation in the kidneys. Additionally, a molecule known as vorapaxar has been reported to suppress macrophages by blocking pathways involved in the AKI to CKD transition.
The teachings of this article will contribute to the development of additional therapeutic strategies against the AKI-CKD transition!
Meng, X. et al. (2022) Motor role of macrophages in the transition from acute renal failure to chronic renal failure. Chinese medical journal. doi.org/10.1097/CM9.0000000000002100.
#Researchers #highlight #impact #macrophage #subtypes #transition #acute #kidney #injury #CKD