Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A variant of ASIC2 mediates sodium retention in nephrotic syndrome.

ABSTRACT: Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention leading to edema. This sodium retention is usually attributed to epithelial sodium channel (ENaC) activation after plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped (CC) rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We then identified a truncated variant of acid-sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when coexpressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that the expression of the truncated ASIC2b in the kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but not in any of the patients with other renal diseases. We have therefore identified a variant of ASIC2b responsible for the renal Na retention in the pathological context of INS.

SUBMITTER: Fila M

PROVIDER: S-EPMC8410034 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Characteristics of sodium and water retention in rats with nephrotic syndrome induced by puromycin aminonucleoside.

Project description:IntroductionNephrotic syndrome (NS) is characterized by renal sodium and water retention. The mechanisms are not fully elucidated.MethodsThe NS rat model was established by single intraperitoneal injection of 100 mg/kg puromycin aminonucleoside (PAN). The plasma electrolyte level and urinary sodium excretion were monitored dynamically. The changes of some sodium transporters, including epithelial Na+ channel (ENaC), Na+/H+ exchanger 3 (NHE3), Na+-K+-2Cl- cotransporter 2 (NKCC2) and Na+-Cl- cotransporter (NCC) in renal cortex at different time points and the level of peripheral circulation factors were detected.ResultsThe urinary sodium excretion of the model group increased significantly on the first day, then decreased compared with the control group, and there was no significant difference between the model group and the control group on the 12th day. The changes of peripheral circulation factors were not obvious. Some sodium transporters in renal cortex increased in varying degrees, while NKCC2 decreased significantly compared with the control group.ConclusionsThe occurrence of NS edema may not be related to the angiotensin system. The decrease of urinary sodium excretion is independent of the development of albuminuria. During the 18 days of observation, it can be divided into three stages: sodium retention, sodium compensation, and simple water retention. The mechanism is related to the increased expression of α-ENaC, γ-ENaC, NHE3 and NCC in a certain period of time, the compensatory decrease of NKCC2 expression and the continuous increase of aquaporin 2 (AQP2) expression.

| S-EPMC10599035 | biostudies-literature

Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome.

Project description:AimSodium retention is the hallmark of nephrotic syndrome (NS) and mediated by the proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases. Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in NS. However, a proof of the essential role of plasmin in experimental NS is lacking.MethodsWe used a genetic mouse model of NS based on an inducible podocin knockout (Bl6-Nphs2tm3.1Antc *Tg(Nphs1-rtTA*3G)8Jhm *Tg(tetO-cre)1Jaw or nphs2Δipod ). These mice were crossed with plasminogen deficient mice (Bl6-Plgtm1Jld or plg-/- ) to generate double knockout mice (nphs2Δipod *plg-/- ). NS was induced after oral doxycycline treatment for 14 days and mice were followed for subsequent 14 days.ResultsUninduced nphs2Δipod *plg-/- mice had normal kidney function and sodium handling. After induction, proteinuria increased similarly in both nphs2Δipod *plg+/+ and nphs2Δipod *plg-/- mice. Western blot revealed the urinary excretion of plasminogen and plasmin in nphs2Δipod *plg+/+ mice which were absent in nphs2Δipod *plg-/- mice. After the onset of proteinuria, amiloride-sensitive natriuresis was increased compared to the uninduced state in both genotypes. Subsequently, urinary sodium excretion dropped in both genotypes leading to an increase in body weight and development of ascites. Treatment with the serine protease inhibitor aprotinin prevented sodium retention in both genotypes.ConclusionsThis study shows that mice lacking urinary plasminogen are not protected from ENaC-mediated sodium retention in experimental NS. This points to an essential role of other urinary serine proteases in the absence of plasminogen.

| S-EPMC7688481 | biostudies-literature

Secretion of the epithelial sodium channel chaperone PCSK9 from the cortical collecting duct links sodium retention with hypercholesterolemia in nephrotic syndrome.

Project description:The proprotein PCSK9 functions as a chaperone for the epithelial sodium channel in the cortical collecting duct (CCD), is highly expressed in the liver, and plays a significant role in the pathogenesis of hypercholesterolemia. Lower levels of PCSK9 expression also occur in the normal kidney and intestine. Here, we found increased PCSK9 expression in the CCD of biopsies of patients with primary glomerular disease and explored a possible relationship with hypercholesterolemia of nephrotic syndrome. Significantly elevated serum PCSK9 and cholesterol levels were noted in two models of focal and segmental glomerulosclerosis, the Rrm2b-/- mouse and the Buffalo/Mna rat. Increased expression of PCSK9 in the kidney occurred when liver expression was reduced in both models. The impact of reduced or increased PCSK9 in the CCD on hypercholesterolemia in nephrotic syndrome was next studied. Mice with selective deficiency of PCSK9 expression in the collecting duct failed to develop hypercholesterolemia after injection of nephrotoxic serum. Blocking epithelial sodium channel activity with Amiloride in Rrm2b-/- mice resulted in increased expression of its chaperone PCSK9 in the CCD, followed by elevated plasma levels and worsening hypercholesterolemia. Thus, our data suggest that PCSK9 in the kidney plays a role in the initiation of hypercholesterolemia in nephrotic syndrome and make a case for depletion of PCSK9 early in patients with nephrotic syndrome to prevent the development of hypercholesterolemia.

| S-EPMC7719084 | biostudies-literature

Nephrotic syndrome and adrenal insufficiency caused by a variant in SGPL1.

Project description:Little is known about the molecular pathogenesis of congenital nephrotic syndrome in association with primary adrenal insufficiency. Most recently, three groups found concurrently the underlying genetic defect in the gene sphingosine-1-phosphate lyase 1 (SGPL1) and called the disease nephrotic syndrome type 14 (NPHS14). In this report we have performed whole-exome sequencing and identified a new homozygous variant in SGPL1, p.Arg340Trp, in a girl with nephrotic syndrome and Addison's disease. Her brother died previously with the same phenotype and hyperpigmentation of the skin. We reviewed the reported cases and concluded that NPHS14 is a clinically recognizable syndrome. The discovery of this syndrome may contribute to the diagnosis and description of additional patients who could benefit from treatment, genetic counseling and screening for related comorbidities. Until now, patients with congenital nephrotic syndrome associated with primary adrenal insufficiency have been treated as having two different diseases; however, the treatment for patients with NPHS14 should be unique, possibly targeting the sphingolipid metabolism.

| S-EPMC6070023 | biostudies-literature

Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome.

Project description:The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses. Despite the identification of key structural proteins in the glomerular capillary loop which may contribute to defects in ultrafiltration, many of the disease mechanisms of nephrotic syndrome remain unresolved. In this study, we show that the glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Angptl4(-/-) mice that were injected with lipopolysaccharide (LPS) or nephritogenic antisera developed markedly less proteinuria than did control mice. Angptl4 secreted from podocytes in some forms of nephrotic syndrome lacks normal sialylation. When we fed the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) to NPHS2-Angptl4 transgenic rats it increased the sialylation of Angptl4 and decreased albuminuria by more than 40%. These results suggest that podocyte-secreted Angptl4 has a key role in nephrotic syndrome.

| S-EPMC3021185 | biostudies-literature

Congenital nephrotic syndrome.

Project description:Congenital nephrotic syndrome (CNS) is a rare kidney disorder characterized by heavy proteinuria, hypoproteinemia, and edema starting soon after birth. The majority of cases are caused by genetic defects in the components of the glomerular filtration barrier, especially nephrin and podocin. CNS may also be a part of a more generalized syndrome or caused by a perinatal infection. Immunosuppressive medication is not helpful in the genetic forms of CNS, and kidney transplantation is the only curative therapy. Before the operation, management of these infants largely depends on the magnitude of proteinuria. In severe cases, daily albumin infusions are required to prevent life-threatening edema. The therapy also includes hypercaloric diet, thyroxin and mineral substitution, prevention of thrombotic episodes, and prompt management of infectious complications. The outcome of CNS patients without major extrarenal manifestations is comparable with other patient groups after kidney transplantation.

| S-EPMC2753773 | biostudies-other

Venous Thrombosis in Nephrotic Syndrome.

Project description:The column in this issue is supplied by Whitney Sharp, D.O., and Juan Jose Olivero, M.D. Dr. Sharp is chief medical resident in internal medicine at Houston Methodist Hospital and earned her Doctor of Osteopathic Medicine degree at Nova Southeastern University in Fort Lauderdale, Florida. Dr. Olivero is a nephrologist at Houston Methodist Hospital and a member of the hospital's Nephrology Training Program. He obtained his medical degree from the University of San Carlos School of Medicine in Guatemala, Central America, and completed his residency and nephrology fellowship at Baylor College of Medicine in Houston, Texas.

| S-EPMC6217559 | biostudies-other

Novel gelsolin variant as the cause of nephrotic syndrome and renal amyloidosis in a large kindred.

Project description:Familial Amyloidosis of Finnish type (FAF) is a rare type of autosomal dominant hereditary amyloidosis associated with genetic variants of gelsolin. Three amyloidogenic mutations have previously been reported characteristically presenting with ophthalmologic abnormalities, progressive cranial neuropathy and cutis laxa. We report a novel gelsolin variant in a 62-year-old man with nephrotic range proteinuria of 13.2?grams/day as the only presenting symptom. Renal biopsy followed by laser micro-dissection and mass spectrometry showed amyloidosis derived from gelsolin. DNA sequencing revealed the novel gelsolin mutation (c.633C?>?A) encoding p.N211K protein variant. Four of 13 asymptomatic family members were found to be heterozygous for the p.N211K mutation, three of whom had proteinuria of varying degree including one who proceeded to renal biopsy and was confirmed to have renal amyloidosis. Follow-up of these cases might give us more insight into pathogenicity and potential treatment strategy of this atypical presentation of gelsolin amyloidosis.

| S-EPMC4061150 | biostudies-literature

Congenital nephrotic syndrome in a Hispanic Guatemalan newborn associated with a NPHS1 variant: A case report.

Project description:Congenital nephrotic syndrome (CNS) is an autosomal recessive disorder usually detected in the first 3 months of life when the syndromes effects manifest, including edema and a failure to gain weight. A baby boy was admitted to the Neonatal Intensive Care Unit for prematurity (35 weeks) with unremarkable maternal prenatal laboratory tests. The patient had persistent systemic hypertension, hypoproteinemia, hypoalbuminemia and nephrotic range proteinuria. CNS was diagnosed, and genetic testing showed a homozygous variant, c.3024A>G (AGA>AGG) in exon 22 of the nephrin locus. Bioinformatics analysis suggested the genetic condition was likely a result of malfunctional DNA binding sites of transcription factors FOXL1 and FOXC1.

| S-EPMC8652645 | biostudies-literature

Familial forms of nephrotic syndrome.

Project description:The recent discovery of genes involved in familial forms of nephrotic syndrome represents a break-through in nephrology. To date, 15 genes have been characterized and several new loci have been identified, with a potential for discovery of new genes. Overall, these genes account for a large fraction of familial forms of nephrotic syndrome, but they can also be recognized in 10-20% of sporadic cases. These advances increase diagnostic and therapeutic potentials, but also add higher complexity to the scenario, requiring clear definitions of clinical, histopathological and molecular signatures. In general, genetic forms of nephrotic syndrome are resistant to common therapeutic approaches (that include steroids and calcineurin inhibitors) but, in a few cases, drug response or spontaneous remission suggest a complex pathogenesis. Finally, syndromic variants can be recognized on the basis of the associated extra-renal manifestations. In this educational review, clinical, histological and molecular aspects of various forms of familial nephrotic syndrome have been reviewed in an attempt to define a rational diagnostic approach. The proposed model focuses on practical and economic issues, taking into consideration the impossibility of using genetic testing as starting diagnostic tool. The final objective of this review is to outline a diagnostic flow-chart for clinicians and geneticists and to generate a rational scheme for molecular testing.

| S-EPMC6904408 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data