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Frontiers in Nephrology 2024Congenital nephrotic syndrome (CNS) is a severe kidney disorder characterized by edema, massive proteinuria, and hypoalbuminemia that manifests or within three months...
BACKGROUND
Congenital nephrotic syndrome (CNS) is a severe kidney disorder characterized by edema, massive proteinuria, and hypoalbuminemia that manifests or within three months after birth. CNS affects 1-3 per 100,000 children, primarily associated with genetic variants and occasionally with infections. Genetic analysis is the first-line method for diagnosis. The most common founder variants have been identified in European populations, often resulting in end-stage kidney disease by 1-2 years of age.
CASE-DIAGNOSIS/TREATMENT
A female full-term neonate, without prenatal signs of kidney disease, was admitted to Rapa Nui (Eastern Island) Hospital at the age of 2 months due to bronchial obstruction. She presented fever, oliguria, edema, urine protein-to-creatinine ratio (UPCR) 433.33, and hypoalbuminemia (0.9 g/dL). She was transferred to a mainland Chilean hospital following CNS diagnosis. Viral screening detected cytomegalovirus (CMV) positivity in both blood and urine. A kidney biopsy revealed interstitial nephritis and diffuse podocyte damage and the tissue PCR resulted negative for CMV. Interviews with the parents revealed consanguinity, suggestive of hereditary CNS. Genetic analysis identified the Maori founder variant, c.2131C>A (p.R711S), in homozygosis. The patient received albumin infusions and antiviral therapy, being discharged when she was 5 months old, with improved laboratory parameters evidenced by UPCR 28.55, albumin 2.5 g/dL, and cholesterol 190 mg/dL. Subsequent clinical monitoring was conducted through virtual and in-person consultations. At her last follow-up at 4 years 2 months old, she presented UPCR 16.1, albumin 3.3 g/dl and cholesterol 220 mg/dL, maintaining normal kidney function and adequate growth.
CONCLUSIONS
To our knowledge, this represents the first case of CNS in Chile carrying a variant associated with prolonged kidney survival. As described in the Maori population, the patient exhibited a less severe clinical course compared to classical patients. Genetic testing for the Maori founder variant in CNS patients related to the New Zealand population, could impact management decisions and potentially prevent the need for nephrectomies.
PubMed: 38808020
DOI: 10.3389/fneph.2024.1379061 -
PloS One 2024Dach1 is highly expressed in normal podocytes, but this expression rapidly disappears after podocyte injury. To investigate the role of Dach1 in podocytes in vivo, we...
Dach1 is highly expressed in normal podocytes, but this expression rapidly disappears after podocyte injury. To investigate the role of Dach1 in podocytes in vivo, we analyzed global, podocyte-specific, and inducible Dach1 knockout mice. Global Dach1 knockout (Dach1-/-) mice were assessed immediately after birth because they die within a day. The kidneys of Dach1-/- mice were slightly smaller than those of control mice but maintained a normal structure and normal podocyte phenotypes, including ultrastructure. To study the role of Dach1 in mature podocytes, we generated Dach1 knockout mice by mating Dach1fl/fl mice with Nphs1-Cre or ROSA-CreERT2 mice. Due to inefficient Cre recombination, only a small number of podocytes lacked Dach1 staining in these mice. However, all eleven Nphs1-Cre/Dach1fl/fl mice displayed abnormal albuminuria, and seven (63%) of them developed focal segmental glomerulosclerosis. Among 13 ROSA-CreERT2/Dach1fl/fl mice, eight (61%) exhibited abnormal albuminuria after treatment with tamoxifen, and five (38%) developed early sclerotic lesions. These results indicate that while Dach1 does not determine the fate of differentiation into podocytes, it is indispensable for maintaining the normal integrity of mature podocytes.
Topics: Animals; Podocytes; Mice; Mice, Knockout; Albuminuria; Cell Differentiation; Glomerulosclerosis, Focal Segmental; Eye Proteins
PubMed: 38805434
DOI: 10.1371/journal.pone.0303910 -
BioRxiv : the Preprint Server For... May 2024Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target...
Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy1α1 as a specific kidney fibroblast marker. Gucy1α1 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy1α1 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfrβ) and vimentin (Vim), Gucy1α1 did not overlap with off-target populations such as podocytes. Notably, Gucy1α1 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY1α1 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy1α1 elevation in activated Pdgfrβ-, Vim- and alpha smooth muscle actin (αSma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy1α1 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY1α1 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.
PubMed: 38798483
DOI: 10.1101/2024.05.15.594404 -
Organogenesis Dec 2024This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced...
This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 10 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production.
Topics: Animals; Doxorubicin; Humans; Adipose Tissue; Rats, Sprague-Dawley; Male; Kidney Diseases; Rats; Mesenchymal Stem Cells; Neovascularization, Physiologic; Mesenchymal Stem Cell Transplantation; Oxidative Stress; Kidney; Fibrosis; Vascular Endothelial Growth Factor A; Stromal Cells; Angiogenesis
PubMed: 38796830
DOI: 10.1080/15476278.2024.2356339 -
International Journal of Molecular... May 2024Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function....
Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.
Topics: Humans; Podocytes; Lab-On-A-Chip Devices; Kidney Glomerulus; Glomerulonephritis; Glomerular Filtration Barrier; Glomerulonephritis, Membranous; Glomerulonephritis, IGA; Permeability; Endothelial Cells; Lupus Nephritis; Cell Survival; Nephrosis, Lipoid
PubMed: 38791159
DOI: 10.3390/ijms25105121 -
Biomedicines Apr 2024Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized... (Review)
Review
Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.
PubMed: 38790940
DOI: 10.3390/biomedicines12050978 -
Experimental and Molecular Pathology May 2024Little information is available concerning protein expression of the free fatty acid receptor 2 (FFAR2), especially in tumours. Therefore, the aim of the present study...
OBJECTIVE
Little information is available concerning protein expression of the free fatty acid receptor 2 (FFAR2), especially in tumours. Therefore, the aim of the present study was to comprehensively characterise the expression profile of FFAR2 in a large series of human normal and neoplastic tissues using immunohistochemistry thus providing a basis for further in-depth investigations into its potential diagnostic or therapeutic importance.
METHODS
We developed a novel rabbit polyclonal anti-FFAR2 antibody, 0524, directed against the C-terminal region of human FFAR2. Antibody specificity was confirmed via Western blot analyses and immunocytochemistry using the FFAR2-expressing cell line BON-1 and FFAR2-specific small interfering RNA as well as native and FFAR2-transfected HEK-293 cells. The antibody was then used for immunohistochemical analyses of various formalin-fixed, paraffin-embedded specimens of normal and neoplastic human tissues.
RESULTS
In normal tissues, FFAR2 was mainly present in distinct cell populations of the cerebral cortex, follicular cells and C cells of the thyroid, cardiomyocytes of the heart, bronchial epithelia and glands, hepatocytes and bile duct epithelia of the liver, gall bladder epithelium, exocrine and β-cells of the endocrine pancreas, glomerular mesangial cells and podocytes as well as collecting ducts of the kidney, intestinal mucosa (particularly enteroendocrine cells), prostate epithelium, seminiferous tubules of the testicles, and placental syncytiotrophoblasts. In neoplastic tissues, FFAR2 was particularly prevalent in papillary thyroid carcinomas, parathyroid adenomas, and gastric, colon, pancreatic, hepatocellular, cholangiocellular, urinary bladder, breast, cervical, and ovarian carcinomas.
CONCLUSIONS
We generated and characterised a novel rabbit polyclonal anti-human FFAR2 antibody that is well-suited for visualising FFAR2 expression in human routine pathology tissues. This antibody is also suitable for Western blot and immunocytochemistry experiments. To our knowledge, this antibody enabled the first broad FFAR2 protein expression profile in various normal and neoplastic human tissues.
PubMed: 38788249
DOI: 10.1016/j.yexmp.2024.104902 -
Cells May 2024Induction of the adenosine receptor A (AAR) expression in diabetic glomeruli correlates with an increased abundance of its endogenous ligand adenosine and the...
Pharmacological Blockade of the Adenosine A Receptor Is Protective of Proteinuria in Diabetic Rats, through Affecting Focal Adhesion Kinase Activation and the Adhesion Dynamics of Podocytes.
Induction of the adenosine receptor A (AAR) expression in diabetic glomeruli correlates with an increased abundance of its endogenous ligand adenosine and the progression of kidney dysfunction. Remarkably, AAR antagonism protects from proteinuria in experimental diabetic nephropathy. We found that AAR antagonism preserves the arrangement of podocytes on the glomerular filtration barrier, reduces diabetes-induced focal adhesion kinase (FAK) activation, and attenuates podocyte foot processes effacement. In spreading assays using human podocytes in vitro, adenosine enhanced the rate of cell body expansion on laminin-coated glass and promoted peripheral pY397-FAK subcellular distribution, while selective AAR antagonism impeded these effects and attenuated the migratory capability of podocytes. Increased phosphorylation of the Myosin2A light chain accompanied the effects of adenosine. Furthermore, when the AAR was stimulated, the cells expanded more broadly and more staining of pS19 myosin was detected which co-localized with actin cables, suggesting increased contractility potential in cells planted onto a matrix with a stiffness similar to of the glomerular basement membrane. We conclude that AAR is involved in adhesion dynamics and contractile actin bundle formation, leading to podocyte foot processes effacement. The antagonism of this receptor may be an alternative to the intervention of glomerular barrier deterioration and proteinuria in the diabetic kidney disease.
Topics: Podocytes; Animals; Humans; Proteinuria; Rats; Receptor, Adenosine A2B; Cell Adhesion; Focal Adhesion Protein-Tyrosine Kinases; Diabetes Mellitus, Experimental; Male; Diabetic Nephropathies; Adenosine A2 Receptor Antagonists; Adenosine; Cell Movement; Phosphorylation; Myosin Light Chains
PubMed: 38786068
DOI: 10.3390/cells13100846 -
Scientific Reports May 2024Natriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by...
Natriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by binding to natriuretic peptide receptors 1 and 2 (NPR1/2), whereas natriuretic peptide receptor 3 (NPR3) acts as a clearance receptor that removes NPs from the circulation. Mouse studies have shown that local NP-signaling in the kidney glomerulus is important for the maintenance of renal homeostasis. In this study we examined the expression of NPR3 in kidney tissue and explored its involvement in renal physiology and disease by generating podocyte-specific knockout mice (NPR3) as well as by using an NPR3 inhibitor (NPR3i) in rodent models of kidney disease. NPR3 was highly expressed by podocytes. NPR3 animals showed no renal abnormalities under healthy conditions and responded similarly to nephrotoxic serum (NTS) induced glomerular injury. However, NPR3i showed reno-protective effects in the NTS-induced model evidenced by decreased glomerulosclerosis and reduced podocyte loss. In a ZSF1 rat model of diabetic kidney injury, therapy alone with NPR3i did not have beneficial effects on renal function/histology, but when combined with losartan (angiotensin receptor blocker), NPR3i potentiated its ameliorative effects on albuminuria. In conclusion, these results suggest that NPR3 may contribute to kidney disease progression.
Topics: Animals; Receptors, Atrial Natriuretic Factor; Mice; Mice, Knockout; Podocytes; Rats; Kidney Glomerulus; Male; Disease Models, Animal; Kidney Diseases; Losartan; Diabetic Nephropathies
PubMed: 38782980
DOI: 10.1038/s41598-024-61603-4 -
Metabolic Analysis and Renal Protective Effects of Linagliptin and Empagliflozin in Alport Syndrome.Kidney360 May 2024We previously demonstrated that Empagliflozin (Empa), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduces intrarenal lipid accumulation and slows kidney function...
BACKGROUND
We previously demonstrated that Empagliflozin (Empa), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduces intrarenal lipid accumulation and slows kidney function decline in experimental Alport syndrome (AS). In this study, we aimed to evaluate the renal protective benefits of Linagliptin (Lina), a dipeptidyl peptidase-4 (DPP4) inhibitor in AS and compare it to Empa.
METHODS
Metabolite distribution in kidney cortices was assessed using mass spectrometry imaging. We examined albuminuria and histological changes in kidneys from AS mice treated with Lina and/or Empa or vehicle.
RESULTS
Several metabolites, including adrenic acid (AdA) and glucose, were increased in renal cortices of AS mice when compared to wildtype (WT) mice, while eicosapentaenoic acid (EPA) levels were decreased. In addition, a redistribution of AdA from the glomerular compartment in WT mice to the tubulointerstitial compartment in AS mice was observed. Both Lina and Empa treatments were found to reduce albuminuria, to extend the survival of AS mice for about 10 days, and to decrease glomerulosclerosis and tubulointerstitial fibrosis compared to WT mice. There were no significant differences with regard to the renal phenotype observed between Empa and Lina treated AS mice, and the combination of Lina and Empa was not superior to individual treatments. In vitro experiments revealed that DPP4 is expressed in podocytes and tubular cells derived from both AS and WT mice. Differently from what we have reported for Empa, Lina treatment was found to reduce glucose-driven respiration in AS tubular cells, but not in AS podocytes.
CONCLUSIONS
Renal expression patterns and spatial distribution of several metabolites differ in AS compared to WT mice. While Lina and Empa treatments similarly partially slow the progression of kidney disease in AS, the metabolic mechanisms conferring the protective effect may be different.
PubMed: 38781016
DOI: 10.34067/KID.0000000000000472