Macrophages promote Fibrinogenesis during kidney injury (original) (raw)
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Macrophages and Renal Fibrosis
Seminars in Nephrology, 2010
Renal fibrosis is a key determinant of the progression of renal disease irrespective of the original cause and thus can be regarded as a final common pathway that dictates eventual outcome. The development of renal fibrosis involves many cellular and molecular mediators including leukocytes, myofibroblasts, cytokines, and growth factors, as well as metalloproteinases and their endogenous inhibitors. Study of experimental and human renal disease has shown the involvement of macrophages in renal fibrosis resulting from diverse disease processes. Recent work exploring the nature of both circulating monocytes and tissue macrophages has highlighted their multifaceted phenotype and this impacts their role in renal fibrosis in vivo. In this review we outline the key players in the fibrotic response of the injured kidney and discuss the role of monocytes and macrophages in renal scarring.
Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair
Journal of the American Society of Nephrology, 2011
The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1-and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifn␥-stimulated, bone marrowderived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFN␥-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFN␥-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFN␥-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.
The Impact of Versatile Macrophage Functions on Acute Kidney Injury and Its Outcomes
Frontiers in Physiology, 2019
Acute kidney injury (AKI) is a common and devastating clinical condition with a high morbidity and mortality rate and is associated with a rapid decline of kidney function mostly resulting from the injury of proximal tubules. AKI is typically accompanied by inflammation and immune activation and involves macrophages (Mφ) from the beginning: The inflamed kidney recruits "classically" activated (M1) Mφ, which are initially poised to destroy potential pathogens, exacerbating inflammation. Of note, they soon turn into "alternatively" activated (M2) Mφ and promote immunosuppression and tissue regeneration. Based on their roles in kidney recovery, there is a growing interest to use M2 Mφ and Mφ-modulating agents therapeutically against AKI. However, it is pertinent to note that the clinical translation of Mφ-based therapies needs to be critically reviewed and questioned since Mφ are functionally plastic with versatile roles in AKI and some Mφ functions are detrimental to the kidney during AKI. In this review, we discuss the current state of knowledge on the biology of different Mφ subtypes during AKI and, especially, on their role in AKI and assess the impact of versatile Mφ functions on AKI based on the findings from translational AKI studies.
Macrophage diversity in renal injury and repair
Journal of Clinical Investigation, 2008
Monocyte-derived macrophages can determine the outcome of the immune response and whether this response contributes to tissue repair or mediates tissue destruction. In addition to their important role in immune-mediated renal disease and host defense, macrophages play a fundamental role in tissue remodeling during embryonic development, acquired kidney disease, and renal allograft responses. This review summarizes macrophage phenotype and function in the orchestration of kidney repair and replacement of specialized renal cells following injury. Recent advances in our understanding of macrophage heterogeneity in response to their microenvironment raise new and exciting therapeutic possibilities to attenuate or conceivably reverse progressive renal disease in the context of fibrosis. Furthermore, parallels with pathological processes in many other organs also exist. Nonstandard abbreviations used: AT1, angiotensin II receptor type 1; MCP-1, monocyte chemoattractant protein 1; SHIP, Src homology 2-containing inositol-5′-phosphatase; Ym-1, chitinase 3-like 3. Conflict of interest: The authors have declared that no conflict of interest exists.
Pathway from Acute Kidney Injury to Chronic Kidney Disease: Molecules Involved in Renal Fibrosis
International Journal of Molecular Sciences
Acute kidney injury (AKI) is one of the main conditions responsible for chronic kidney disease (CKD), including end-stage renal disease (ESRD) as a long-term complication. Besides short-term complications, such as electrolyte and acid-base disorders, fluid overload, bleeding complications or immune dysfunctions, AKI can develop chronic injuries and subsequent CKD through renal fibrosis pathways. Kidney fibrosis is a pathological process defined by excessive extracellular matrix (ECM) deposition, evidenced in chronic kidney injuries with maladaptive architecture restoration. So far, cited maladaptive kidney processes responsible for AKI to CKD transition were epithelial, endothelial, pericyte, macrophage and fibroblast transition to myofibroblasts. These are responsible for smooth muscle actin (SMA) synthesis and abnormal renal architecture. Recently, AKI progress to CKD or ESRD gained a lot of interest, with impressive progression in discovering the mechanisms involved in renal fibr...
AJP: Renal Physiology, 2013
Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targetin...
International Journal of Molecular Sciences, 2020
(1) Background: Successful treatment of acute kidney injury (AKI)-induced chronic kidney disease (CKD) is unresolved. We aimed to characterize the time-course of changes after contralateral nephrectomy (Nx) in a model of unilateral ischemic AKI-induced CKD with good translational utility. (2) Methods: Severe (30 min) left renal ischemia-reperfusion injury (IRI) or sham operation (S) was performed in male Naval Medical Research Institute (NMRI) mice followed by Nx or S one week later. Expression of proinflammatory, oxidative stress, injury and fibrotic markers was evaluated by RT-qPCR. (3) Results: Upon Nx, the injured kidney hardly functioned for three days, but it gradually regained function until day 14 to 21, as demonstrated by the plasma urea. Functional recovery led to a drastic reduction in inflammatory infiltration by macrophages and by decreases in macrophage chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) mRNA and most injury markers. However, without Nx, a marked upregulation of proinflammatory (TNF-α, IL-6, MCP-1 and complement-3 (C3)); oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2) and fibrosis (collagen-1a1 (Col1a1) and fibronectin-1 (FN1)) genes perpetuated, and the injured kidney became completely fibrotic. Contralateral Nx delayed the development of renal failure up to 20 weeks. (4) Conclusion: Our results suggest that macrophage activation is involved in postischemic renal fibrosis, and it is drastically suppressed by contralateral nephrectomy ameliorating progression.
Scientific reports, 2018
Renal artery stenosis (RAS) caused by narrowing of arteries is characterized by microvascular damage. Macrophages are implicated in repair and injury, but the specific populations responsible for these divergent roles have not been identified. Here, we characterized murine kidney F4/80CD64 macrophages in three transcriptionally unique populations. Using fate-mapping and parabiosis studies, we demonstrate that CD11b/c are long-lived kidney-resident (KRM) while CD11cMϕ, CD11cMϕ are monocyte-derived macrophages. In a murine model of RAS, KRM self-renewed, while CD11cMϕ and CD11cMϕ increased significantly, which was associated with loss of peritubular capillaries. Replacing the native KRM with monocyte-derived KRM using liposomal clodronate and bone marrow transplantation followed by RAS, amplified loss of peritubular capillaries. To further elucidate the nature of interactions between KRM and peritubular endothelial cells, we performed RNA-sequencing on flow-sorted macrophages from Sha...