AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance ...between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll-like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a
mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor-associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a
mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.
Abstract
Context
The bone-derived hormone fibroblast growth factor (FGF) 23 controls phosphate homeostasis and urinary phosphate excretion. FGF23 plasma levels increase in the early stage of renal ...insufficiency to prevent hyperphosphatemia. Recent evidence suggests that this increase has effects on cardiac and immune cells that compromise patients’ health. Patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported to have higher FGF23 concentrations than other patients with similar renal function. The significance of this finding has remained unknown.
Methods and Results
Analyzing the FGF23 plasma levels in 434 patients with ADPKD and 355 control subjects with a measured glomerular filtration rate (mGFR) between 60 and 120 mL/min per 1.73 m2, we confirmed that patients with ADPKD had higher FGF23 plasma concentrations than controls. Remarkably, this difference did not translate into renal phosphate leakage. Using different assays for FGF23, we found that this discrepancy was explained by a predominant increase in the cleaved C-terminal fragment of FGF23, which lacks phosphaturic activity. We found that FGF23 plasma concentration independently correlated with the severity of cystic liver disease in ADPKD. We observed that, in contrast to control liver tissues, the cystic liver from patients with ADPKD markedly expressed FGF23 messenger RNA and protein. In line with this finding, the surgical reduction of polycystic liver mass was associated with a decrease in FGF23 plasma levels independently of any modification in mGFR, phosphate, or iron status.
Conclusion
Our findings demonstrate that severely polycystic livers produce FGF23 and increase levels of circulating FGF23 in patients with ADPKD.
Increased FGF23 plasma levels in patients with autosomal dominant polycystic kidney disease with preserved renal function are linked to the production of cleaved FGF23 fragments by the cystic liver.
The loss of functional nephrons after kidney injury triggers the compensatory growth of the remaining ones to allow functional adaptation. However, in some cases, these compensatory events activate ...signaling pathways that lead to pathological alterations and chronic kidney disease. Little is known about the identity of these pathways and how they lead to the development of renal lesions. Here, we combined mouse strains that differently react to nephron reduction with molecular and temporal genome-wide transcriptome studies to elucidate the molecular mechanisms involved in these events. We demonstrated that nephron reduction led to 2 waves of cell proliferation: the first one occurred during the compensatory growth regardless of the genetic background, whereas the second one occurred, after a quiescent phase, exclusively in the sensitive strain and accompanied the development of renal lesions. Similarly, clustering by coinertia analysis revealed the existence of 2 waves of gene expression. Interestingly, we identified type I interferon (IFN) response as an early (first-wave) and specific signature of the sensitive (FVB/N) mice. Activation of type I IFN response was associated with G1/S cell cycle arrest, which correlated with p21 nuclear translocation. Remarkably, the transient induction of type I IFN response by poly(I:C) injections during the compensatory growth resulted in renal lesions in otherwise-resistant C57BL6 mice. Collectively, these results suggest that the early molecular and cellular events occurring after nephron reduction determine the risk of developing late renal lesions and point to type I IFN response as a crucial event of the deterioration process.
Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic ...resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer’s disease, AD), automaticity (Parkinson’s disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.
Women with gestational diabetes (GD) have reduced antioxidant capacity; however, the relationship between maternal diet, maternal biochemical capacity, breast milk concentration, and infant intake ...has not been adequately explored in the literature. An exploration of underlying mechanism(s) is warranted, particularly for nutrient antioxidants impacted by maternal intake. These nutrients may provide a means for modifying maternal and infant antioxidant capacity. Oxygen radical absorbance capacity (ORAC), alpha-tocopherol, ascorbic acid, and beta-carotene concentrations were measured in breast milk of women with and without GD. Plasma, three-day diet records, and breast milk were collected at 6 to 8 weeks postpartum. Student's
-test was used to compare breast milk ORAC, nutrient antioxidant concentration and plasma ORAC between women with and without GD. Pearson correlations were used to determine associations among antioxidant concentrations in breast milk and dietary antioxidant intake. Breast milk antioxidant concentrations were associated with maternal intake of beta-carotene (
= 0.629,
= 0.005). Breast milk and plasma ORAC and antioxidant vitamin concentrations were not significantly different between GD and NG women. Breast milk ORAC associated with breast milk alpha-tocopherol for NG (
= 0.763,
= 0.010), but not GD women (
= 0.385,
= 0.35), and with breast milk ascorbic acid for GD (
= 0.722,
= 0.043) but not NG women (
= 0.141,
= 0.70; interaction
= 0.041). In GD participants, breast milk ORAC was significantly associated with plasma ORAC (
= 0.780,
= 0.039). ORAC and antioxidant vitamin concentrations in breast milk in women with GD were comparable to women with NG; however, the relationships between breast milk ORAC and vitamin concentrations differed in GD versus NG women for alpha-tocopherol and ascorbic acid.
Source rocks are expected to become increasingly important in the upcoming years for oil and gas production as well as for the storage of greenhouse gases. These rocks are bedded and heterogeneous ...media, composed of minerals, kerogen, and pore space. One of the most challenging issues is to better define the pore space, including pore size distribution, pore volume fraction, pore connectivity, and pore affinity for various fluids. The aim of this study is to achieve such relevant parameters using X-ray and neutron scattering technique complementarity. Rock thin blades cut normal to the bedding plane preserve sample integrity and allow their measurements in both techniques. Two-dimensional scattering patterns show anisotropy, due to preferential orientation of lamellar minerals, which allows us to assess an order parameter. This parameter is a valuable tool for mechanical and transport properties. A model based on a three-phase system (minerals, kerogen, and pores) is developed through the study of scattering length density of each component within both radiations. The model allows us to fit both X-ray and neutron 1D data using the same model parameters. This latter is then considered as selective. It allows us to extract the kerogen mass density, the kerogen pore size distribution and its associated volume fraction, and the chemical nature of kerogen pore content. This methodology has been applied to a series of five source rocks of increasing maturities from Barnett Shale Play and Montney-Doig formations. Mature samples show a kerogen density of ∼1.6 g·cm–3, a pore radius distribution centered on 0.5–0.7 nm accounting for a pore volume fraction of ∼0.01–0.04. These kerogen nanopores are filled with light condensed hydrocarbons. However, the overmature kerogen exhibits a mass density of 1.74 g·cm–3, an additional pore radius distribution centered around 3.5 nm with a pore volume fraction of 0.002, and an empty pore space. All these parameters are in agreement with Rock-Eval pyrolysis measurements and literature data on similar source rocks. These results pointed out that the three-phase model associated with X-ray and neutron complementarity could be applied to in situ studies.
We propose and demonstrate experimentally the transfer of one spatial degree of freedom of a laser beam onto another one. Using a multi-plane light conversion device (MPLC) and a modal analysis, we ...designed a passive setup with immediate response which couples a displacement and tilt in the transverse plane to a longitudinal shift of the focus point of a beam. With this design, we demonstrated a shift of the focal point of the output beam by 4 zR along the propagation axis.
Impairment of the intestinal barrier and subsequent microbial translocation (MT) may be involved in chronic immune activation, which plays a central role in HIV pathogenesis. Th17 cells are critical ...to prevent MT. The aim of the study was to investigate, in patients with primary HIV infection (PHI), the early relationship between the Th17/Treg ratio, monocyte activation and MT and their impact on the T-cell activation set point, which is known to predict disease progression. 27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. At baseline, the Th17/Treg ratio strongly negatively correlated with the proportion of activated CD8 T cells expressing CD38/HLA-DR or Ki-67. Also, the Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1RA, two markers of monocyte activation. In untreated patients, the Th17/Treg ratio at baseline negatively correlated with CD8 T-cell activation at month 6 defining the T-cell activation set point (% HLA-DR(+)CD38(+) and %Ki-67(+)). Soluble CD14 and IL-1RA plasma levels also predicted the T-cell activation set point. Levels of I-FABP, a marker of mucosal damages, were similar to healthy controls at baseline but increased at month 6. No decrease in anti-endotoxin core antibody (EndoCAb) and no peptidoglycan were detected during PHI. In addition, 16S rDNA was only detected at low levels in 2 out 27 patients at baseline and in one additional patient at M6. Altogether, data support the hypothesis that T-cell and monocyte activation in PHI are not primarily driven by systemic MT but rather by viral replication. Moreover, the "innate immune set point" defined by the early levels of sCD14 and IL-1RA might be powerful early surrogate markers for disease progression and should be considered for use in clinical practice.
Persistent immune activation plays a central role in the pathogenesis of HIV disease. Besides natural regulatory T cells (nTregs), 'double negative' T cells shown to exhibit regulatory properties ...could be involved in the control of harmful immune activation. The aim of this study was to analyze, in patients with primary HIV infection (PHI), the relationship between CD4(+)CD25(+)CD127(low)FoxP3(+) nTregs or CD3(+)CD4(-)CD8(-) double negative T cells and systemic immune activation.
A prospective longitudinal study of patients with early PHI.
Twenty-five patients were included. Relationships between frequency of Treg subsets and T-cell activation, assessed on fresh peripheral blood mononuclear cells, were analyzed using nonparametric tests. Cytokine production by double negative T cells was assessed following anti-CD3/anti-CD28 stimulation.
No relationship was found between T-cell activation and frequencies of nTregs. In contrast, a strong negative relationship was found at baseline between the proportion of double negative T cells and the proportion of activated CD8 T cells coexpressing CD38 and HLA-DR (P = 0.005) or expressing Ki-67 (P = 0.002). In addition, the frequency of double negative T cells at baseline negatively correlated with the frequency of HLA-DR(+)CD38(+)CD8(+) T cells at month 6, defining the immune activation set point (P = 0.031). High proportions of stimulated double negative T cells were found to produce the immunosuppressive cytokines transforming growth factor-β1 and/or IL-10.
The proportion of double negative T cells at baseline was found to be predictive of the immune activation set point. Our data strongly suggest that double negative T cells may control immune activation in PHI. This effect might be mediated through the production of TGF-β1/IL-10 known to downmodulate immune activation.
PDF
