Generation of SARS-CoV-2 Spike Pseudotyped Virus for Viral Entry and Neutralization Assays: A 1-Week Protocol.

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus requires reliable assays for studying viral entry mechanisms which remains poorly understood. This knowledge is important for the development of therapeutic approaches to control SARS-CoV-2 infection by permitting the screening for neutralizing antibodies and other agents that can block infection. This is particularly important for patients who are at high risk for severe outcomes related to COVID-19.

APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis.

Lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. If and how endogenous APOL1 may alter mitochondrial function by the modifying cellular lipid metabolism is unknown.

Noninvasive assessment of radiation-induced renal injury in mice.

Purpose: The kidney is a radiosensitive late-responding normal tissue. Injury is characterized by radiation nephropathy and decline of glomerular filtration rate (GFR). The current study aimed to compare two rapid and cost-effective methodologies of assessing GFR against more conventional biomarker measurements.

Pharmacokinetics of Gepotidacin in Subjects With Normal Hepatic Function and Hepatic Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open-label, multicenter, 2-part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects.

The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification.

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases.

Thiazide-Sensitive NCC (Sodium-Chloride Cotransporter) in Human Metabolic Syndrome: Sodium Sensitivity and Potassium-Induced Natriuresis.

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome.

Sphingosine-1-Phosphate Metabolism and Signaling in Kidney Diseases.

In the past few decades, sphingolipids and sphingolipid metabolites have gained attention because of their essential role in the pathogenesis and progression of kidney diseases. Studies in models of experimental and clinical nephropathies have described accumulation of sphingolipids and sphingolipid metabolites, and it has become clear that the intracellular sphingolipid composition of renal cells is an important determinant of renal function. Proper function of the glomerular filtration barrier depends heavily on the integrity of lipid rafts, which include sphingolipids as key components.

Osteopontin and LDLR Are Upregulated in Hearts of Sudden Cardiac Death Victims With Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus.

Diabetes mellitus (DM) is associated with increased risk of sudden cardiac death (SCD), particularly in patients with heart failure with preserved ejection fraction (HFpEF). However, there are no known biomarkers in the population with DM and HFpEF to predict SCD risk. This study was designed to test the hypothesis that osteopontin (OPN) and some proteins previously correlated with OPN, low-density lipoprotein receptor (LDLR), dynamin 2 (DNM2), fibronectin-1 (FN1), and 2-oxoglutarate dehydrogenase-like (OGDHL), are potential risk markers for SCD, and may reflect modifiable molecular pathways in patients with DM and HFpEF.

Modular Microphysiological System for Modeling of Biologic Barrier Function.

Microphysiological systems, also known as organs-on-chips, are microfluidic devices designed to model human physiology . Polydimethylsiloxane (PDMS) is the most widely used material for organs-on-chips due to established microfabrication methods, and properties that make it suitable for biological applications such as low cytotoxicity, optical transparency, gas permeability. However, absorption of small molecules and leaching of uncrosslinked oligomers might hinder the adoption of PDMS-based organs-on-chips for drug discovery assays.

Lipid Metabolism Gets in a JAML during Kidney Disease.

It is still unclear if the ability of key regulators of actin cytoskeletal remodeling to influence lipid metabolism contributes to kidney injury. In this issue of Cell Metabolism, Fu et al. (2020) show that junctional adhesion molecule-like (JAML) is a novel mediator of glomerular disease progression while suggesting a direct link between defects in cell adhesion and lipotoxicity.

Lipid deposition and metaflammation in diabetic kidney disease.

A critical link between metabolic disorders and a form of low-grade systemic and chronic inflammation has been recently established and named 'Metaflammation'. Metaflammation has been recognized as a key mediator of both microvascular and macrovascular complications of diabetes and as a significant contributor to the development of diabetic kidney disease (DKD). The goal of this review is to summarize the contribution of diabetes-induced inflammation and the related signaling pathways to diabetic complications, with a particular focus on how innate immunity and lipid metabolism influence each other.

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS.

Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier.

Nuclear Osteopontin Is a Marker of Advanced Heart Failure and Cardiac Allograft Vasculopathy: Evidence From Transplant and Retransplant Hearts.

Background: Heart transplant is the gold standard therapy for patients with advanced heart failure. Over 5,500 heart transplants are performed every year worldwide. Cardiac allograft vasculopathy (CAV) is a common complication post-heart transplant which reduces survival and often necessitates heart retransplantation.

Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome.

Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes.

The Vicious Cycle of Renal Lipotoxicity and Mitochondrial Dysfunction.

The kidney is one of the most energy-demanding organs that require abundant and healthy mitochondria to maintain proper function. Increasing evidence suggests a strong association between mitochondrial dysfunction and chronic kidney diseases (CKDs). Lipids are not only important sources of energy but also essential components of mitochondrial membrane structures.

Crosstalk Between Lipids and Mitochondria in Diabetic Kidney Disease.

Purpose Of Review: The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression.

Recent Findings: Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al.

Identification of glomerular and podocyte-specific genes and pathways activated by sera of patients with focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) accounts for about 40% of all nephrotic syndrome cases in adults. The presence of several potential circulating factors has been suggested in patients with primary FSGS and particularly in patients with recurrent disease after transplant. Irrespectively of the nature of the circulating factors, this study was aimed at identifying early glomerular/podocyte-specific pathways that are activated by the sera of patients affected by FSGS.

Lipid mediators of insulin signaling in diabetic kidney disease.

Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival.

Regulation of the amount of ceramide-1-phosphate synthesized in differentiated human podocytes.

Sphingolipids have important functions as structural components of cells but they also function as signaling molecules regulating different cellular processes such as apoptosis, cell proliferation, cell migration, cell division and inflammation. Hence, a tight regulation of the sphingolipid homeostasis is essential to maintain proper cellular functions. Mammalian ORMDL proteins are orthologues of the yeast ORM1/2 proteins, which regulate ceramide synthesis in yeast.

Single-Center Investigation of the Pharmacokinetics of WCK 4282 (Cefepime-Tazobactam Combination) in Renal Impairment.

WCK 4282 is a combination product of cefepime (FEP) and tazobactam (TAZ) in a 1:1 ratio currently under development for the treatment of multidrug-resistant Gram-negative bacterial infections. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 4282 in 48 subjects with various degrees of renal function. Subjects were categorized on the basis of their Cockcroft-Gault equation-estimated creatinine clearance (CL).

Safety and efficacy of antihyperglycaemic agents in diabetic kidney disease.

Diabetic kidney disease (DKD) is the major contributor to the mortality and the financial burden of diabetes, accounting for approximately 50% of the cases of end-stage renal disease (ESRD) in the developed world. Several studies have already demonstrated that achieving blood pressure targets in DKD with agents blocking the renin-angiotensin system confer superior renoprotection when compared to other agents. However, the effects on renal outcomes of antihyperglycaemic agents in these patients have not been reported or studied broadly until recent years.

SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo.

Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway.

Background: Patients with chronic kidney disease (CKD) and coincident heart failure with preserved ejection fraction (HFpEF) may constitute a distinct HFpEF phenotype. Osteopontin (OPN) is a biomarker of HFpEF and predictive of disease outcome. We recently reported that OPN blockade reversed hypertension, mitochondrial dysfunction, and kidney failure in Col4a3 mice, a model of human Alport syndrome.