The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice

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The renal mononuclear phagocytic system, conventionally composed of macrophages (Mø) and dendritic cells (DCs), plays a central role in health and disease of the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically separate research tracks and the lack of experimental tools to specifically study the roles of these cells in vivo, have generated confusion and controversy, however, regarding their immunologic function in the kidney. This brief review provides an appraisal of the current state of knowledge of the renal mononuclear phagocytic system interpreted from the perspective of immunologic function. Physical characteristics, ontogeny, and known functions of the main subsets of renal mononuclear phagocytes as they relate to homeostasis, surveillance against injury and infection, and immune-mediated inflammatory injury and repair within the kidney are described. Gaps and inconsistencies in current knowledge are used to create a roadmap of key questions to be answered in future research.

Section: Functions Of Rmoph In Surveillance Tolerance and Tissue Cymentioning

confidence: 90%

Section: Plasticity Of Function Of Rmoph During Renal Injury and Repairmentioning

confidence: 99%

The Renal Mononuclear Phagocytic System

Nelson

Rees

Griffin

et al. 2012

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“…[30][31][32][33][34][35][36][37][38] In particular, HO1 is essential for the regulation of redox pathways and catabolism of heme. 31,39 Here, we show that endotoxin preconditioning upregulated HO1 and SIRT1 in F4/80-positive macrophages (Figure 8).…”

Section: Macrophages In the Kidneys Of Preconditioned Mice Have Incrementioning

confidence: 99%

The Macrophage Mediates the Renoprotective Effects of Endotoxin Preconditioning

Hato¹,

Winfree²,

Kalakeche³

et al. 2015

Preconditioning is a preventative approach, whereby minimized insults generate protection against subsequent larger exposures to the same or even different insults. In immune cells, endotoxin preconditioning downregulates the inflammatory response and yet, preserves the ability to contain infections. However, the protective mechanisms of preconditioning at the tissue level in organs such as the kidney remain poorly understood. Here, we show that endotoxin preconditioning confers renal epithelial protection in various models of sepsis in vivo. We also tested the hypothesis that this protection results from direct interactions between the preconditioning dose of endotoxin and the renal tubules. This hypothesis is on the basis of our previous findings that endotoxin toxicity to nonpreconditioned renal tubules was direct and independent of immune cells. Notably, we found that tubular protection after preconditioning has an absolute requirement for CD14-expressing myeloid cells and particularly, macrophages. Additionally, an intact macrophage CD14-TRIF signaling pathway was essential for tubular protection. The preconditioned state was characterized by increased macrophage number and trafficking within the kidney as well as clustering of macrophages around S1 proximal tubules. These macrophages exhibited increased M2 polarization and upregulation of redox and ironhandling molecules. In renal tubules, preconditioning prevented peroxisomal damage and abolished oxidative stress and injury to S2 and S3 tubules. In summary, these data suggest that macrophages are essential mediators of endotoxin preconditioning and required for renal tissue protection. Preconditioning is, therefore, an attractive model to investigate novel protective pathways for the prevention and treatment of sepsis. 26: 134726: -136226: , 201526: . doi: 10.1681 Gram-negative sepsis is a formidable and challenging clinical condition that carries very high morbidity and mortality. Indeed, it is estimated that mortality from sepsis can exceed 70%, especially when complicated by organ failure. 1 AKI is frequently seen in patients with sepsis and dramatically increases morbidity and mortality. To date, treatment of sepsis and sepsis-induced AKI remains supportive and relies primarily on antibiotic therapy, fluid and electrolyte management, and hemodynamic support. 2 One hallmark of sepsis is widespread tissue oxidative stress. Uncontrolled reactive oxygen species rapidly react with all biologic macromolecules and result in deleterious tissue damage, including organ failure. We and others have shown that the endotoxin (LPS) receptor Tolllike receptor 4 (TLR4) and coreceptor CD14 are expressed in renal tubules and upregulated in sepsis and ischemia. [3][4][5][6][7][8] We also showed that systemic endotoxin is freely filtered and interacts with S1 J Am Soc Nephrol

“…31,49 The expression of HO-1 is always correlated with a better prognosis after ischemic damage. [50][51][52] We found that mice injected with GTCs showed a strong upregulation of HO-1 2 days after renal damage induction. This finding suggests that HO-1 upregulation induced by GTCs could be involved in kidney protection from IRI.…”

Section: Discussionmentioning

confidence: 76%

Renal Cells from Spermatogonial Germline Stem Cells Protect against Kidney Injury

Chiara

Fagoonee

Bruno

et al. 2014

Spermatogonial stem cells reside in specific niches within seminiferous tubules and continuously generate differentiating daughter cells for production of spermatozoa. Although spermatogonial stem cells are unipotent, these cells are able to spontaneously convert to germline cell-derived pluripotent stem cells (GPSCs) in vitro. GPSCs have many properties of embryonic stem cells and are highly plastic, but their therapeutic potential in tissue regeneration has not been fully explored. Using a novel renal epithelial differentiation protocol, we obtained GPSC-derived tubular-like cells (GTCs) that were functional in vitro, as demonstrated through transepithelial electrical resistance analysis. In mice, GTCs injected after ischemic renal injury homed to the renal parenchyma, and GTC-treated mice showed reduced renal oxidative stress, tubular apoptosis, and cortical damage and upregulated tubular expression of the antioxidant enzyme hemeoxygenase-1. Six weeks after ischemic injury, kidneys of GTC-treated mice had less fibrosis and inflammatory infiltrate than kidneys of vehicle-treated mice. In conclusion, we show that GPSCs can be differentiated into functionally active renal tubular-like cells that therapeutically prevent chronic ischemic damage in vivo, introducing the potential utility of GPSCs in regenerative cell therapy. AKI is a common complication characterized by a rapid reduction in kidney function that results in failure to maintain fluid. AKI is a potentially reversible disease. However, some patients recover incompletely from AKI, and these patients either continue undergoing dialysis or progress to CKD. Moreover, development of CKD can lead to ESRD. One of the main causes of AKI is ischemia/reperfusion injury (IRI). 1 IRI is a pathologic condition characterized by an initial restriction of blood supply followed by the subsequent restoration of perfusion and concomitant reoxygenation that is frequently associated with an exacerbation of tissue injury and a strong inflammatory response. 2 The cells within the renal parenchyma that suffer the most damage upon kidney ischemia are the proximal tubular cells. This is likely due to the presence of a brush border on these cells that increases cell surface area and sensitizes them to damage.The recent discovery of the ability to reprogram adult cells into pluripotent stem cells (iPSCs) has profound therapeutic implications for diseases involving tissue damage and degeneration. Derivation of pluripotent stem cells from an adult source avoids several ethical concerns of obtaining such cells from embryos. However, efficient generation of iPSCs typically requires transduction of cells with reprogramming factors, including potent proto-oncogenes that can limit their therapeutic uses. 3 The existence of inherent epigenetic differences between iPSCs and regular embryonic stem cells (ESCs) can adversely affect iPSCs functionality. 4,5