Regulatory T cells in acute and chronic kidney diseases.

Foxp3-expressing CD4 regulatory T cells (Tregs) make up one subset of the helper T cells (Th) and are one of the major mechanisms of peripheral tolerance. Tregs prevent abnormal activation of the immune system throughout the lifespan, thus protecting from autoimmune and inflammatory diseases. Recent studies have elucidated the role of Tregs beyond autoimmunity.

IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury.

CD4Foxp3 regulatory T cells (Tregs) protect the kidney during AKI. We previously found that IL-2, which is critical for Treg homeostasis, upregulates the IL-33 receptor (ST2) on CD4 T cells, thus we hypothesized that IL-2 and IL-33 cooperate to enhance Treg function. We found that a major subset of Tregs in mice express ST2, and coinjection of IL-2 and IL-33 increased the number of Tregs in lymphoid organs and protected mice from ischemia-reperfusion injury (IRI) more efficiently than either cytokine alone.

The spleen as a bidirectional signal transducer in acute kidney injury.

In acute kidney injury models, the lung is damaged through an interleukin-6-dependent inflammatory response. Clinically, development of lung injury requiring mechanical ventilation markedly increases in-hospital acute kidney injury mortality. Andres-Hernando et al.

The Influence of Hemodialysis on T Regulatory Cells: A Meta-Analysis and Systematic Review.

Aims: The study aimed to determine whether the available literature supports a positive or negative influence of dialysis on regulatory T-cells (Tregs).

Methods: We performed a systematic search and a meta-analysis. Mean differences in Tregs number of chronic kidney disease stages G5 on dialysis patients (CKD G5D) and healthy controls (HCs) were compared.

Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.

We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.

Both PD-1 ligands protect the kidney from ischemia reperfusion injury.

Acute kidney injury (AKI) is a common problem in hospitalized patients that enhances morbidity and mortality and promotes the development of chronic and end-stage renal disease. Ischemia reperfusion injury (IRI) is one of the major causes of AKI and is characterized by uncontrolled renal inflammation and tubular epithelial cell death. Our recent studies demonstrated that regulatory T cells (Tregs) protect the kidney from ischemia reperfusion-induced inflammation and injury.

Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury.

Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of five G protein- coupled receptors (S1P1-S1P5Rs), regulates cell survival and lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720, attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on proximal tubule (PT) cells, independent of the canonical lymphopenic effects of S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI.

Expanding role of T cells in acute kidney injury.

Purpose Of Review: Recent advances in T cell biology have shed light on the role of T cell subsets in the pathogenesis of acute kidney injury (AKI). The purpose of this review is to harness our understanding of recent advances in T cell biology in tissue injury and repair and provide a mechanistic insight into the role of T cells in the inflammation of AKI.

Recent Findings: New specific reagents and genetic animal models have led to advances in our understanding of the role of T cell subsets involved in renal injury.

Regulatory T cells in AKI.

Human AKI is manifested by inflammation, and an early feature in the pathogenesis is the accumulation of immune cells in the kidney. To understand the pathophysiology of AKI, results from animal models have shown a causal relation between the leukocyte activation and infiltration to the kidney after kidney ischemia-reperfusion. Blocking the activation or trafficking of proinflammatory leukocytes into the kidney preserves renal function and histologic integrity.

Dendritic cells tolerized with adenosine A₂AR agonist attenuate acute kidney injury.

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A₂AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A₂AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A₂AR agonists.

Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection.

Regulatory T cells (Tregs) suppress the innate inflammation associated with kidney ischemia-reperfusion injury (IRI), but the mechanism is not well understood. Tregs express CD73, the final enzyme involved in the production of extracellular adenosine, and activation of the adenosine 2A receptor (A(2A)R) on immune cells suppresses inflammation and preserves kidney function after IRI. We hypothesized that Treg-generated adenosine is required to block innate immune responses in kidney IRI and that the Treg-generated adenosine would signal through A(2A)Rs on inflammatory cells and, in an autocrine manner, on Tregs themselves.

Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury.

Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN). C-C chemokine receptor (CCR)2 regulates monocyte/macrophage migration into injured tissues. However, the direct role of CCR2-mediated monocyte/macrophage recruitment in diabetic kidney disease remains unclear.

Pathogenesis of acute kidney injury: foundation for clinical practice.

The pathogenesis of acute kidney injury (AKI) is complex, involving such factors as vasoconstriction, leukostasis, vascular congestion, cell death, and abnormal immune modulators and growth factors. Many targeted clinical therapies have failed, are inconclusive, or have yet to be tested. Given the complexity of the pathogenesis of AKI, it may be naive to expect that one therapeutic intervention would have success.

Profiling of fatty acids released during calcium-induced mitochondrial permeability transition in isolated rabbit kidney cortex mitochondria.

Increases in intracellular Ca(2+) during cellular stress often lead to the mitochondrial permeability transition (MPT). We examined changes in fatty acids (FAs) released from isolated renal cortical mitochondria subjected to Ca(2+)-induced MPT. Exposing mitochondria to Ca(2+) stimulated mitochondrial swelling and release of FAs such as arachidonic (20:4) and docosahexenoic acids which increased 71% and 32%, respectively, and linoleic (18:2) which decreased 23% compared to controls.

Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney.

Reperfusion following ischemia is associated with acute kidney injury and inflammation. Using a mouse model, we exposed the kidney to a nonlethal period of ischemia, rendering it refractory to future ischemia-induced dysfunction. This ischemic preconditioning is partially mediated by Treg lymphocytes that suppress immune responses.

Immune mechanisms and novel pharmacological therapies of acute kidney injury.

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and both innate and adaptive immunity contribute to the pathogenesis. Kidney resident cells promote inflammation after IRI by increasing endothelial cell adhesion molecule expression and vascular permeability. Kidney epithelial cells bind complement and express toll-like receptors and resident and infiltrating cells produce cytokines/chemokines.

Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury.

Both innate and adaptive mechanisms participate in the pathogenesis of kidney ischemia-reperfusion injury (IRI), but the role of regulatory immune mechanisms is unknown. We hypothesized that the anti-inflammatory effects of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) protect against renal IRI. Partial depletion of Tregs with an anti-CD25 mAb potentiated kidney damage induced by IRI.

Inflammation in acute kidney injury.

Ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI) and evidence supporting the involvement of both innate and adaptive immunity in renal IRI has accumulated in recent years. In addition to leukocytes, kidney endothelial cells promote inflammation after IRI by increasing adhesion molecule expression and vascular permeability. Kidney tubular epithelial cells increase complement binding and upregulate toll-like receptors, both of which lead to cytokine/chemokine production in IRI.

Decreased iPLA2gamma expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis.

Our previous studies showed that renal proximal tubular cells (RPTC) express Ca(2+)-independent phospholipase A(2)gamma (iPLA(2)gamma) in endoplasmic reticulum (ER) and mitochondria and that iPLA(2)gamma prevents and/or repairs lipid peroxidation induced by oxidative stress. Our present studies determined the importance of iPLA(2)gamma in mitochondrial and cell function using an iPLA(2)gamma-specific small hairpin ribonucleic acid (shRNA) adenovirus. iPLA(2)gamma expression and activity were decreased in the ER by 24 h and in the mitochondria by 48 h compared with scrambled shRNA adenovirus-treated cells.

Extracellular signal-regulated kinase activation mediates mitochondrial dysfunction and necrosis induced by hydrogen peroxide in renal proximal tubular cells.

Although tubular necrosis in acute renal failure is associated with excessive production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), the mechanism of ROS-induced cell necrosis remains poorly understood. In this study, we examined the role of the extracellular signaling-regulated kinase (ERK) pathway in H2O2-induced necrosis of renal proximal tubular cells (RPTC) in primary culture. Exposure of 60 to 70% confluent RPTC to 1 mM H2O2 for 3 h resulted in 44% necrotic cell death, as measured by trypan blue uptake, and inactivation of mitogen-activated protein kinase kinase (MEK), the upstream activator of ERK, by either 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126) or 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059) or overexpression of dominant-negative mutant of MEK1, inhibited cell death.

Heparin-binding epidermal growth factor and Src family kinases in proliferation of renal epithelial cells.

Our recent studies have shown that proliferation of renal proximal tubular cells (RPTC) in the absence of growth factors requires activation of the epidermal growth factor (EGF) receptor. We sought to identify the endogenous EGF receptor ligand and investigate the mechanism(s) by which RPTC proliferate in different models. RPTC expressed both pro- and cleaved forms of heparin-binding epidermal growth factor (HB-EGF) and several metalloproteinases (MMP-2, -3, -9, and ADAM10, ADAM17) that have been reported to cleave HB-EGF.

Role of Ca2+-independent phospholipase A2gamma in Ca2+-induced mitochondrial permeability transition.

Our laboratory previously demonstrated Ca2+-independent phospholipase A2gamma (iPLA2gamma) is localized to mitochondria and that iPLA2 inhibition blocks cisplatin-induced caspase-mediated apoptosis. Whereas the mitochondrial permeability transition (MPT) is a key control point for apoptosis, the role of mitochondrial iPLA2gamma in MPT has not been established. In the present study, we addressed this issue.