National Unified Renal Translational Research Enterprise: Idiopathic Nephrotic Syndrome (NURTuRE-INS) study.

Background: Idiopathic nephrotic syndrome (INS) is a heterogenous disease and current classification is based on observational responses to therapies or kidney histology. The National Unified Renal Translational Research Enterprise (NURTuRE)-INS cohort aims to facilitate novel ways of stratifying INS patients to improve disease understanding, therapeutics and design of clinical trials.

Methods: NURTuRE-INS is a prospective cohort study of children and adults with INS in a linked biorepository.

Contrasting consequences of podocyte insulin-like growth factor 1 receptor inhibition.

Insulin signaling to the glomerular podocyte via the insulin receptor (IR) is critical for kidney function. In this study we show that near-complete knockout of the closely related insulin-like growth factor 1 receptor (IGF1R) in podocytes is detrimental, resulting in albuminuria and podocyte cell death . In contrast, partial podocyte IGF1R knockdown confers protection against doxorubicin-induced podocyte injury.

Adiponectin Reduces Glomerular Endothelial Glycocalyx Disruption and Restores Glomerular Barrier Function in a Mouse Model of Type 2 Diabetes.

Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs).

Multivariate canonical correlation analysis identifies additional genetic variants for chronic kidney disease.

Chronic kidney diseases (CKD) have genetic associations with kidney function. Univariate genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN), two complementary kidney function markers. However, it is unknown whether additional SNPs for kidney function can be identified by multivariate statistical analysis.

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.

Background: Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively.

Consistent traffic noise impacts few fitness-related traits in a field cricket.

Background: Anthropogenic habitat change is occurring rapidly, and organisms can respond through within-generation responses that improve the match between their phenotype and the novel conditions they encounter. But, plastic responses can be adaptive or maladaptive and are most likely to be adaptive only when contemporary conditions reasonably mimic something experienced historically to which a response has already evolved. Noise pollution is a ubiquitous anthropogenic stressor that accompanies expanding urbanization.

A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome.

Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum.

Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome.

Gene therapy for kidney diseases has proven challenging. Adeno-associated virus (AAV) is used as a vector for gene therapy targeting other organs, with particular success demonstrated in monogenic diseases. We aimed to establish gene therapy for the kidney by targeting a monogenic disease of the kidney podocyte.

X chromosome drive is constrained by sexual selection and influences ornament evolution.

Experimental evolution provides an integrative method for revealing complex interactions among evolutionary processes. One such interaction involves sex-linked selfish genetic elements and sexual selection. X-linked segregation distorters, a type of selfish genetic element, influence sperm transmission to increase in frequency and consequently alter the population sex ratio and the opportunity for sexual selection, while sexual selection may impact the spread of X-linked distorters.

Renal tissue engineering for regenerative medicine using polymers and hydrogels.

Chronic Kidney Disease (CKD) is a growing worldwide problem, leading to end-stage renal disease (ESRD). Current treatments for ESRD include haemodialysis and kidney transplantation, but both are deemed inadequate since haemodialysis does not address all other kidney functions, and there is a shortage of suitable donor organs for transplantation. Research in kidney tissue engineering has been initiated to take a regenerative medicine approach as a potential treatment alternative, either to develop effective cell therapy for reconstruction or engineer a functioning bioartificial kidney.

Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events.

About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS.

Epigenetic Mechanisms and Nephrotic Syndrome: A Systematic Review.

A small subset of people with nephrotic syndrome (NS) have genetically driven disease. However, the disease mechanisms for the remaining majority are unknown. Epigenetic marks are reversible but stable regulators of gene expression with utility as biomarkers and therapeutic targets.

Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx.

The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier. Previously, we showed that mineralocorticoid receptor (MR) activation caused GEnGlx damage and albuminuria. In this study, we investigated whether MR antagonism could limit albuminuria in diabetes and studied the site of action.

The feto-placental metabolome of spontaneous labour is not reproduced following induction of labour.

Introduction: The mechanism for human labour remains poorly understood, limiting our ability to manage complications including spontaneous preterm birth and induction of labour (IOL). The study of fetal signals poses specific challenges. Metabolomic analysis of maternal blood, the cord artery (CA), and cord vein (CV), allows simultaneous interrogation of multiple metabolic pathways associated with different modes of labour onset and birth.

The microvascular endothelial glycocalyx: An additional piece of the puzzle in veterinary medicine.

The endothelial glycocalyx (eGlx) is a critically important structure lining the luminal surface of endothelial cells. There is increasing evidence, in human patients and animal models, for its crucial role in the maintenance of health. Moreover, its damage is associated with the pathogenesis of multiple disease states.

Circulating hyaluronan as a marker of endothelial glycocalyx damage in dogs with myxomatous mitral valve disease and dogs in a hypercoagulable state.

The endothelial glycocalyx (eGlx) lines the luminal surface of endothelial cells, maintaining vascular health. Glycocalyx damage is pathophysiologically important in many diseases across species however few studies have investigated its breakdown in naturally occurring disease in dogs. The aims of the study were to investigate eGlx damage in dogs with myxomatous mitral valve disease (MMVD) diagnosed on echocardiography, and dogs in a hypercoagulable state diagnosed using thromboelastography (TEG), by measuring serum hyaluronan concentrations.

Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations.

Background: Glomerular endothelial cell (GEnC) fenestrations are recognized as an essential component of the glomerular filtration barrier, yet little is known about how they are regulated and their role in disease.

Methods: We comprehensively characterized GEnC fenestral and functional renal filtration changes including measurement of glomerular and GFR in diabetic mice (BTBR ). We also examined and compared human samples.

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model.

Background: Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model.