Renal Ischemia Tolerance Mediated by eIF5A Hypusination Inhibition Is Regulated by a Specific Modulation of the Endoplasmic Reticulum Stress.

Through kidney transplantation, ischemia/reperfusion is known to induce tissular injury due to cell energy shortage, oxidative stress, and endoplasmic reticulum (ER) stress. ER stress stems from an accumulation of unfolded or misfolded proteins in the lumen of ER, resulting in the unfolded protein response (UPR). Adaptive UPR pathways can either restore protein homeostasis or can turn into a stress pathway leading to apoptosis.

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation.

Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT.

Unravelling the sex-specific diversity and functions of adrenal gland macrophages.

Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We define the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and use genetic models to explore the developmental mechanisms yielding macrophage diversity. We define populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identify a female-specific subset with low major histocompatibility complex (MHC) class II expression.

Relationships between Plasma Pyrophosphate, Vascular Calcification and Clinical Severity in Patients Affected by Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE; OMIM 264800) is an autosomal recessive metabolic disorder characterized by progressive calcification in the skin, the Bruch’s membrane, and the vasculature. Calcification in PXE results from a low level of circulating pyrophosphate (PPi) caused by ABCC6 deficiency. In this study, we used a cohort of 107 PXE patients to determine the pathophysiological relationship between plasma PPi, coronary calcification (CAC), lower limbs arterial calcification (LLAC), and disease severity.

Akt Inhibition as Preconditioning Treatment to Protect Kidney Cells against Anoxia.

Lesions issued from the ischemia/reperfusion (I/R) stress are a major challenge in human pathophysiology. Of human organs, the kidney is highly sensitive to I/R because of its high oxygen demand and poor regenerative capacity. Previous studies have shown that targeting the hypusination pathway of eIF5A through GC7 greatly improves ischemic tolerance and can be applied successfully to kidney transplants.

Impact of thermogenesis induced by chronic β3-adrenergic receptor agonist treatment on inflammatory and infectious response during bacteremia in mice.

White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response.

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney.

Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux.

LRRC8/VRAC Channels and the Redox Balance: A Complex Relationship.

More than three decades after their first biophysical description, Volume Regulated Anion Channels (VRACs) still remain challenging to understand. Initially, VRACs were identified as the main pathway for the cell to extrude Cl ions during the regulatory volume decrease (RVD) mechanism contributing to the recovery of normal cell volume. For years, scientists have tried unsuccessfully to find their molecular identity, leading to controversy within the field that only ended in 2014 when two independent groups demonstrated that VRACs were formed by heteromers of LRRC8 proteins.

A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy.

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4 T cells within tumors.

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease.

Introduction: Patients on dialysis and kidney transplant recipients (KTR) present the syndrome of mineral and bone disorders (MBD), which share common traits with monogenic calcifying diseases related to disturbances of the purinergic system. Low plasma levels of inorganic pyrophosphate (PP) and ectopic vascular calcifications belong to these two conditions. This suggests that the purinergic system may be altered in chronic kidney disease with MBD.

KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies.

Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium I current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily.

Modulation of the inflammatory response to LPS by the recruitment and activation of brown and brite adipocytes in mice.

Numerous studies have shown that the recruitment and activation of thermogenic adipocytes, which are brown and beige/brite, reduce the mass of adipose tissue and normalize abnormal glycemia and lipidemia. However, the impact of these adipocytes on the inflammatory state of adipose tissue is still not well understood, especially in response to endotoxemia, which is a major aspect of obesity and metabolic diseases. First, we analyzed the phenotype and metabolic function of white and brite primary adipocytes in response to lipopolysaccharide (LPS) treatment in vitro.

LRRC8/VRAC channels exhibit a noncanonical permeability to glutathione, which modulates epithelial-to-mesenchymal transition (EMT).

Volume-regulated anion channels (VRAC) are chloride channels activated in response to osmotic stress to regulate cellular volume and also participate in other cellular processes, including cell division and cell death. Recently, members of the LRRC8 family have been identified as the main contributors of VRAC conductance. LRRC8/VRAC is permeable to chloride ions but also exhibits significant permeability to various substrates that vary strongly in charge and size.

microRNA-375 regulates glucose metabolism-related signaling for insulin secretion.

Enhanced beta cell glycolytic and oxidative metabolism are necessary for glucose-induced insulin secretion. While several microRNAs modulate beta cell homeostasis, miR-375 stands out as it is highly expressed in beta cells where it regulates beta cell function, proliferation and differentiation. As glucose metabolism is central in all aspects of beta cell functioning, we investigated the role of miR-375 in this process using human and rat islets; the latter being an appropriate model for in-depth investigation.

Vitamin D and Calcium Supplementation Accelerates Randall's Plaque Formation in a Murine Model.

Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth.

TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis.

Matrix Stiffening and EGFR Cooperate to Promote the Collective Invasion of Cancer Cells.

In squamous cell carcinoma (SCC), tissue invasion by collectively invading cells requires physical forces applied by tumor cells on their surrounding extracellular matrix (ECM). Cancer-related ECM is composed of thick collagen bundles organized by carcinoma-associated fibroblasts (CAF) within the tumor stroma. Here, we show that SCC cell collective invasion is driven by the matrix-dependent mechano-sensitization of EGF signaling in cancer cells.

The ABCC6 Transporter: A New Player in Biomineralization.

Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive.

Comparative Effects of Chloride Channel Inhibitors on LRRC8/VRAC-Mediated Chloride Conductance.

Chloride channels play an essential role in a variety of physiological functions and in human diseases. Historically, the field of chloride channels has long been neglected owing to the lack of powerful selective pharmacological agents that are needed to overcome the technical challenge of characterizing the molecular identities of these channels. Recently, members of the LRRC8 family have been shown to be essential for generating the volume-regulated anion channel (VRAC) current, a chloride conductance that governs the regulatory volume decrease (RVD) process.

Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome.

The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of during long-term hypoxia.

The K+ channel TASK1 modulates β-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway.

Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice.