Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice

Ferenbach, David A.; Sheldrake, Tara A.; Dhaliwal, Kevin; Kipari, Tiina; Marson, Lorna; Kluth, David; Hughes, Jeremy

doi:10.1038/ki.2012.207

Cited by 140 publications

(139 citation statements)

References 26 publications

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“…It has already been shown that the protective effects of CL involve CD206 + reparative macrophages. 28 As shown in Figure 8B, CL treatment increased the CD206 + cell fraction, which is known to participate in matrix collagen endocytosis (Supplemental Figure 9). 29 Patent fibrosis could be observed in the glycerol-treated mice, as assessed by collagen III deposits and Masson trichrome staining ( Figure 8C).…”

Section: Rhabdomyolysis Drastically Affects the Kidney Macrophage Phementioning

confidence: 99%

“…CL treatment led to an increase of the CD206 + cell fraction in glycerol-treated mice, an effect previously described after ischemia. 28 We suggest that R1 macrophage depletion could be protective via two additive mechanisms: (1) a general reduction in the accumulation of ECM components such as collagen III and fibronectin (it is known that fibronectin deposits in the kidney interstitium can alter its structure and dampen kidney function, 38 and it has been previously reported that treatment with CL reduced fibronectin deposits in a limb-regeneration model 39 ) and (2) a decrease in the inflammatory response, especially auto-and paracrine chemoattractant loops involving Ccl2, Ccl7, and Il1b.…”

Section: Rhabdomyolysis Drastically Affects the Kidney Macrophage Phementioning

confidence: 99%

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Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Béllière¹,

Casemayou²,

Ducassé³

et al. 2015

Journal of the American Society of Nephrology

126

123

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Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysisinduced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. rophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysisinduced AKI progression and advocate the utility of long-term follow-up for patients with this disease.

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Section: Rhabdomyolysis Drastically Affects the Kidney Macrophage Phementioning

confidence: 99%

Section: Rhabdomyolysis Drastically Affects the Kidney Macrophage Phementioning

confidence: 99%

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Béllière¹,

Casemayou²,

Ducassé³

et al. 2015

Journal of the American Society of Nephrology

126

123

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“…Regardless of these findings, macrophages and dendritic cells derived from monocytes are abundant in kidney injury and play an important role in inflammation, tissue repair, and fibrosis. Ablative studies in several models of kidney interstitial and glomerular disease nevertheless indicate that macrophages significantly contribute to the development of fibrosis (24,28,37,63,67,69,101). It is most likely therefore that monocyte-derived cells in chronic kidney disease drive fibrosis by indirect mechanisms, involving cell-to-cell signaling, although the deposition of nonfibrillar matrix proteins such as fibronectin may contribute in some way to pathological matrix, but this has not been assessed rigorously.…”

Section: Contribution Of Other Cells To Fibrogenesismentioning

confidence: 99%

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

Campanholle

Ligresti

Gharib

et al. 2013

American Journal of Physiology-Cell Physiology

157

154

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Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

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“…15 These observations were made when monocyte/macrophage migration to the kidney, through CCR2-and CX3CR1-dependent mechanisms, was attenuated, 14 or when macrophages were depleted using liposomal clodronate before injury or within 3 days after ischemic insult, respectively. Recent mouse studies have added support to the hypothesis that M1-type, clodronate-sensitive macrophages do participate in initial injury, 11,16 but have also revealed that macrophages are critical for the normal repair processes that inhibit the progression of fibrosis and CKD. [10][11][12] Using several sophisticated mouse models, Lin et al demonstrated that macrophages responding to renal injury produce and release the Wnt ligand Wnt7b that acts on injured and regenerating TECs to promote their continuation through the cell cycle and regeneration of the tubule basement membrane, thus re-establishing renal function and reducing fibrosis.…”

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confidence: 96%

Macrophage Dynamics in AKI to CKD Progression

Kinsey

2014

Journal of the American Society of Nephrology

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Stemming from the recent and robust clinical data confirming that AKI does indeed increase the likelihood of developing CKD (reviewed by Chawla and Kimmel 1 ), numerous preclinical studies have offered insight into how the transition from AKI to CKD occurs. However, our understanding of this multifactorial process is incomplete. This knowledge is critical if we are to advance therapeutic strategies to combat the detrimental progression of renal injury. The development of CKD is thought to be promoted by an aberrant wound healing response involving tubular epithelial cells (TECs), fibroblasts, pericytes, myofibroblasts, fibrocytes, immune cells, and others, which leads to progressive fibrosis in the kidney and loss of viable nephrons. 2 Previous studies have demonstrated that cell cycle arrest of TECs, 3 as well as epigenetic modifications in renal fibroblasts, 4 are key components in fibrogenesis and the decline in renal function. In an integrated model, 5 cell cycle arrest of TECs leads to unchecked production of profibrotic mediators such as TGF-b and connective tissue growth factor, which induce sustained fibroblast activation and proliferation causing excessive extracellular matrix production, establishment of fibrotic lesions, and CKD. The inflammatory nature of AKI, involving resident cells of the renal mononuclear phagocytic system 6,7 and infiltrating immune cells, 8 suggests that leukocytes and their products would also influence the fate of the injured kidney. For example, sustained leukocyte accumulation and activation inside the kidney would promote extended periods of ischemia due to vascular congestion and may induce direct tubular and endothelial cell damage by the release of inflammatory mediators. Macrophages are among the innate leukocytes that rapidly accumulate in the kidney and promote inflammation in the acute phase of AKI, 9,10 yet macrophages also have a critical role in wound healing as scavengers of proinflammatory cell debris and as promoters of regeneration. 7,10-13 It should be mentioned here that the study of renal resident and/or infiltrating monocytes, macrophages, and dendritic cells is complicated by the overlapping phenotypes and surface marker expression by these different cell types in the kidney during health and injury, 7 and use of the term macrophage to describe the cell types discussed herein is for simplicity.The dual role of macrophages in AKI and subsequent repair and regeneration can be explained by the multiple phenotypes that a macrophage can adopt. There are several different major classifications of macrophage phenotype, including M1 (classically activated) and M2 (alternatively activated) macrophages. Most macrophages fall somewhere in the spectrum between M1 and M2 and may change their characteristics depending on their environment. 13 M1 macrophages are considered proinflammatory and make cytokines such as IL-1, IL-6, and TNF-a, whereas M2 are mainly anti-inflammatory and express arginase, mannose receptor, IL-10, and IL-4 receptor-a. 13 Thus, macrophages disp...

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Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice

Cited by 140 publications

References 26 publications

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

Macrophage Dynamics in AKI to CKD Progression

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