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1.
Front Med (Lausanne) ; 8: 679518, 2021.
Article in English | MEDLINE | ID: mdl-34336885

ABSTRACT

The molecular pathogenesis of diabetic kidney disease progression is complex and remains unresolved. Rho-GAP MYO9A was recently identified as a novel podocyte protein and a candidate gene for monogenic FSGS. Myo9A involvement in diabetic kidney disease has been suggested. Here, we examined the effect of diabetic milieu on Myo9A expression in vivo and in vitro. We determined that Myo9A undergoes S-nitrosylation, a post-translational modification dependent on nitric oxide (NO) availability. Diabetic mice with nodular glomerulosclerosis and severe proteinuria associated with doxycycline-induced, podocyte-specific VEGF 164 gain-of-function showed markedly decreased glomerular Myo9A expression and S-nitrosylation, as compared to uninduced diabetic mice. Immortalized mouse podocytes exposed to high glucose revealed decreased Myo9A expression, assessed by qPCR, immunoblot and immunocytochemistry, and reduced Myo9A S-nitrosylation (SNO-Myo9A), assessed by proximity link assay and biotin switch test, functionally resulting in abnormal podocyte migration. These defects were abrogated by exposure to a NO donor and were not due to hyperosmolarity. Our data demonstrate that high-glucose induced decrease of both Myo9A expression and SNO-Myo9A is regulated by NO availability. We detected S-nitrosylation of Myo9A interacting proteins RhoA and actin, which was also altered by high glucose and NO dependent. RhoA activity inversely related to SNO-RhoA. Collectively, data suggest that dysregulation of SNO-Myo9A, SNO-RhoA and SNO-actin may contribute to the pathogenesis of advanced diabetic kidney disease and may be amenable to therapeutic targeting.

2.
Kidney Int ; 99(5): 1102-1117, 2021 05.
Article in English | MEDLINE | ID: mdl-33412162

ABSTRACT

Focal segmental glomerulosclerosis (FSGS) is a podocytopathy leading to kidney failure, whose molecular cause frequently remains unresolved. Here, we describe a rare MYO9A loss of function nonsense heterozygous mutation (p.Arg701∗) as a possible contributor to disease in a sibling pair with familial FSGS/proteinuria. MYO9A variants of uncertain significance were identified by whole exome sequencing in a cohort of 94 biopsy proven patients with FSGS. MYO9A is an unconventional myosin with a Rho-GAP domain that controls epithelial cell junction assembly, crosslinks and bundles actin and deactivates the small GTPase protein encoded by the RHOA gene. RhoA activity is associated with cytoskeleton regulation of actin stress fiber formation and actomyosin contractility. Myo9A was detected in mouse and human podocytes in vitro and in vivo. Knockin mice carrying the p.Arg701∗MYO9A (Myo9AR701X) generated by gene editing developed proteinuria, podocyte effacement and FSGS. Kidneys and podocytes from Myo9AR701X/+ mutant mice revealed Myo9A haploinsufficiency, increased RhoA activity, decreased Myo9A-actin-calmodulin interaction, impaired podocyte attachment and migration. Our results indicate that Myo9A is a novel component of the podocyte cytoskeletal apparatus that regulates RhoA activity and podocyte function. Thus, Myo9AR701X/+ knock-in mice recapitulate the proband FSGS phenotype, demonstrate that p.R701X Myo9A is an FSGS-causing mutation in mice and suggest that heterozygous loss-of-function MYO9A mutations may cause a novel form of human autosomal dominant FSGS. Hence, identification of MYO9A pathogenic variants in additional individuals with familial or sporadic FSGS is needed to ascertain the gene contribution to disease.


Subject(s)
Glomerulosclerosis, Focal Segmental , Myosins/genetics , Podocytes , Animals , GTPase-Activating Proteins/genetics , Glomerulosclerosis, Focal Segmental/genetics , Humans , Mice , Myosins/metabolism , Phenotype
3.
Front Pharmacol ; 12: 788886, 2021.
Article in English | MEDLINE | ID: mdl-35280251

ABSTRACT

Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte VEGF-A knockdown (VEGFKD ) in diabetic mice and in endothelial nitric oxide synthase knockout mice (eNOS-/- ). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte VEGFKD led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS-/-:VEGFKD mice. VEGFKD diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS-/-:VEGFKD (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGFKD diabetic mice with intact eNOS, whereas VEGFKD induction in eNOS-/-:VEGFKD mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGFKD -induced abnormal S-nitrosylation of specific proteins, including ß3-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure.

4.
Pediatr Nephrol ; 35(6): 959-968, 2020 06.
Article in English | MEDLINE | ID: mdl-31049720

ABSTRACT

The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.


Subject(s)
Exome Sequencing , Kidney Failure, Chronic/genetics , Renal Insufficiency, Chronic/genetics , Adolescent , Age Factors , Branchio-Oto-Renal Syndrome/diagnostic imaging , Branchio-Oto-Renal Syndrome/genetics , Branchio-Oto-Renal Syndrome/pathology , Child , Female , High-Throughput Nucleotide Sequencing , Humans , Infant , Kidney Failure, Chronic/diagnosis , Male , Middle Aged , Mutation , Pedigree , Polymorphism, Single Nucleotide
5.
Nephrol Dial Transplant ; 33(9): 1514-1525, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29635428

ABSTRACT

Background: Vascular endothelial growth factor A (VEGF) is an essential growth factor during glomerular development and postnatal homeostasis. VEGF is secreted in high amounts by podocytes into the primary urine, back-filtered across the glomerular capillary wall to act on endothelial cells. So far it has been assumed that VEGF back-filtration is driven at a constant rate exclusively by diffusion. Methods: In the present work, glomerular VEGF back-filtration was investigated in vivo using a novel extended model based on endothelial fenestrations as surrogate marker for local VEGF concentrations. Single nephron glomerular filtration rate (SNGFR) and/or local filtration flux were manipulated by partial renal mass ablation, tubular ablation, and in transgenic mouse models of systemic or podocytic VEGF overexpression or reduction. Results: Our study shows positive correlations between VEGF back-filtration and SNGFR as well as effective filtration rate under physiological conditions along individual glomerular capillaries in rodents and humans. Conclusion: Our results suggest that an additional force drives VEGF back-filtration, potentially regulated by SNGFR.


Subject(s)
Capillaries/physiopathology , Glomerular Filtration Rate/physiology , Kidney Glomerulus/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Disease Models, Animal , Kidney Glomerulus/physiopathology , Mice , Mice, Knockout , Nephrectomy
7.
Sci Rep ; 7(1): 9833, 2017 08 29.
Article in English | MEDLINE | ID: mdl-28852159

ABSTRACT

Nephrotic syndrome is a common disorder in adults and children whose etiology is largely unknown. Glucocorticoids remain the mainstay of therapy in most cases, though their mechanism of action remains poorly understood. Emerging evidence suggests that immunomodulatory therapies used in nephrotic syndrome directly target the podocytes. To study how steroids directly affect the podocytes in the treatment of proteinuria, we created a mouse model with podocyte-specific deletion of the glucocorticoid receptor. The podocyte-specific glucocorticoid receptor (GR) knockout mice had similar renal function and protein excretion compared to wild type. However, after glomerular injury induced by either LPS or nephrotoxic serum, the podocyte GR knockout mice demonstrated worsened proteinuria compared to wild type. Ultrastructural examination of podocytes confirmed more robust foot process effacement in the knockout animals. Expression of several key slit diaphragm protein was down regulated in pGR KO mice. Primary podocytes isolated from wild type and podocyte GR knockout mice showed similar actin stress fiber staining patterns in unstimulated conditions. Yet, when exposed to LPS, GR knockout podocytes demonstrated fewer stress fibers and impaired migration compared to wild type podocytes. We conclude that the podocyte glucocorticoid receptor is important for limiting proteinuria in settings of podocyte injury.


Subject(s)
Podocytes/metabolism , Proteinuria/etiology , Receptors, Glucocorticoid/deficiency , Actins/metabolism , Alleles , Animals , Cell Movement , Disease Models, Animal , Female , Fluorescent Antibody Technique , Focal Adhesion Kinase 1/genetics , Focal Adhesion Kinase 1/metabolism , Genotype , Lipopolysaccharides/adverse effects , Lipopolysaccharides/immunology , Male , Mice , Mice, Knockout , Nephrotic Syndrome/complications , Nephrotic Syndrome/etiology , Nephrotic Syndrome/metabolism , Nephrotic Syndrome/pathology , Podocytes/ultrastructure , Proteinuria/metabolism , Proteinuria/urine , Receptors, Glucocorticoid/metabolism
8.
Methods Mol Biol ; 1493: 393-399, 2017.
Article in English | MEDLINE | ID: mdl-27787866

ABSTRACT

Podocytes are complex epithelial cells with foot processes that are essential for the integrity and function of the kidney glomerular filters. Podocyte foot processes linked by slit diaphragms constitute signaling platforms that tightly regulate the cell shape and the function of the filtration barrier. Semaphorin (Sema) 3A is a class 3 semaphorin secreted by podocytes that has autocrine and paracrine functions in the kidney. We have shown that Sema3A regulates podocyte shape and that excess Sema3A signaling induces glomerular disease and aggravates diabetic nephropathy. MICAL-1 is an actin-binding protein that mediates Sema3A signals in podocytes. This chapter describes the methods used to examine how Sema3A signaling regulates podocyte shape.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Cell Shape , Cytoskeletal Proteins/physiology , LIM Domain Proteins/physiology , Podocytes/cytology , Semaphorin-3A/physiology , Animals , Cell Line , Cell Line, Transformed , Humans , Mice , Microfilament Proteins , Mixed Function Oxygenases
11.
Nat Commun ; 7: 10822, 2016 Feb 24.
Article in English | MEDLINE | ID: mdl-26905694

ABSTRACT

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.


Subject(s)
Cadherins/genetics , Cell Adhesion/genetics , Cell Movement/genetics , Fibroblasts/metabolism , Nephrotic Syndrome/congenital , Podocytes/metabolism , Zebrafish Proteins/genetics , Animals , Dilatation, Pathologic/genetics , Gene Knockdown Techniques , Hematuria/genetics , Humans , Kidney Tubules/cytology , Kidney Tubules/metabolism , Kidney Tubules/pathology , Lissencephaly/genetics , Mice , Mutation , Nephrotic Syndrome/genetics , Syndrome , Zebrafish , cdc42 GTP-Binding Protein/metabolism , rac1 GTP-Binding Protein/metabolism
12.
J Am Soc Nephrol ; 27(4): 1055-65, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26303067

ABSTRACT

Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests that after podocyte injury, endoplasmic reticulum stress response is activated, but the molecular mechanisms involved are incompletely defined. In a mouse model, we confirmed that podocyte injury induces endoplasmic reticulum stress response and upregulated unfolded protein response pathways, which have been shown to mitigate damage by preventing the accumulation of misfolded proteins in the endoplasmic reticulum. Furthermore, simultaneous podocyte-specific genetic inactivation of X-box binding protein-1 (Xbp1), a transcription factor activated during endoplasmic reticulum stress and critically involved in the untranslated protein response, and Sec63, a heat shock protein-40 chaperone required for protein folding in the endoplasmic reticulum, resulted in progressive albuminuria, foot process effacement, and histology consistent with ESRD. Finally, loss of both Sec63 and Xbp1 induced apoptosis in podocytes, which associated with activation of the JNK pathway. Collectively, our results indicate that an intact Xbp1 pathway operating to mitigate stress in the endoplasmic reticulum is essential for the maintenance of a normal glomerular filtration barrier.


Subject(s)
DNA-Binding Proteins/physiology , Endoplasmic Reticulum Stress/physiology , Podocytes/physiology , Transcription Factors/physiology , Animals , Cells, Cultured , Mice , Regulatory Factor X Transcription Factors , X-Box Binding Protein 1
13.
Nefrologia ; 35(2): 131-8, 2015.
Article in English, Spanish | MEDLINE | ID: mdl-26300505

ABSTRACT

The prevalence of diabetes mellitus increased during the last century and it is estimated that 45% of the patients are not diagnosed. In South America the prevalence of diabetes and chronic kidney disease (CKD) increased, with a great disparity among the countries with respect to access to dialysis. In Ecuador it is one of the main causes of mortality, principally in the provinces located on the coast of the Pacific Ocean. The greatest single cause of beginning dialysis is diabetic nephropathy (DN). Even using the best therapeutic options for DN, the residual risk of proteinuria and of terminal CKD remains high. In this review we indicate the importance of the problem globally and in our region. We analyse relevant cellular and molecular studies that illustrate the crucial significance of glomerular events in DN development and evolution and in insulin resistance. We include basic anatomical, pathophysiological and clinical concepts, with special attention to the role of angiogenic factors such as the vascular endothelial growth factor (VEGF-A) and their relationship to the insulin receptor, endothelial isoform of nitric oxide synthase (eNOS) and angiopoietins. We also propose various pathways that have therapeutic potential in our opinion. Greater in-depth study of VEGF-A and angiopoietins, the state of glomerular VEGF resistance, the relationship of VEGF receptor 2/nephrin, VEGF/insulin receptors/nephrin and the relationship of VEGF/eNOS-NO at glomerular level could provide solutions to the pressing world problem of DN and generate new treatment alternatives.


Subject(s)
Diabetic Nephropathies/metabolism , Vascular Endothelial Growth Factor A/physiology , Angiopoietins/physiology , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Global Health , Humans , Insulin Resistance , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Membrane Proteins/physiology , Nitric Oxide/physiology , Nitric Oxide Synthase Type III/physiology , Receptor, Insulin/physiology , Receptors, Vascular Endothelial Growth Factor/physiology , Signal Transduction
14.
Nefrología (Madr.) ; 35(2): 131-138, mar.-abr. 2015. ilus
Article in Spanish | IBECS | ID: ibc-139278

ABSTRACT

La prevalencia de diabetes mellitus aumentó en el último siglo y se estima que el 45%de los pacientes, no estarían diagnosticados. En Sudamérica la prevalencia de diabetes y de enfermedad renal crónica (ERC) incrementó, existiendo gran disparidad entre los países respecto al acceso a diálisis. En Ecuador es una de las principales causas de mortalidad, principalmente en las provincias ubicadas en la costa del océano Pacífico. La mayor causa aislada de ingreso a diálisis es la nefropatía diabética (ND). Aun utilizando las mejores opciones terapéuticas para la ND, el riesgo residual de proteinuria y de ERC terminal permanece elevado. En esta revisión describimos la importancia del problema en el mundo y en nuestra región Analizamos estudios moleculares y celulares relevantes que indican la crucial importancia de eventos glomerulares en el desarrollo y en la evolución de la ND y en la insulinorresistencia. Incluimos conceptos anatómicos, fisiopatológicos y clínicos básicos, desarrollando especial énfasis en el rol de factores angiogénicos como el factor de crecimiento vascular endotelial(VEGF-A) y su relación con el receptor de insulina, la sintasa endotelial de óxido nítrico-óxidonítrico (eNOS) y las angiopoietinas. En el transcurso del texto proponemos diversas vías, que a nuestro entender tienen potencial terapéutico. Profundizar en el estudio del VEGF-A y la sangiopoietinas, el estado de VEGF resistencia glomerular, la relación del receptor 2 de VEGF/nefrina, VEGF/receptores de insulina/nefrina, la relación VEGF/eNOS-ON a nivel glomerular podría aportar soluciones al acuciante problema de la ND en el mundo y generar nuevas alternativas de tratamiento (AU)


The prevalence of diabetes mellitus increased during the last century and it is estimated that45% of the patients are not diagnosed. In South America the prevalence of diabetes and chronic kidney disease (CKD) increased, with a great disparity among the countries with respect to access to dialysis. In Ecuador it is one of the main causes of mortality, principally in the provinces located on the coast of the Pacific Ocean. The greatest single cause of beginning dialysis is diabetic nephropathy (DN). Even using the best therapeutic options for DN, the residual risk of proteinuria and of terminal CKD remains high. In this review we indicate the importance of the problem globally and in our region. We analyse relevant cellular and molecular studies that illustrate the crucial significance of glomerular events in DN development and evolution and in insulin resistance. We include basic anatomical, pathophysiological and clinical concepts, with special attention to the role of angiogenic factors such as the vascular endothelial growth factor (VEGF-A) and their relationship to the insulin receptor, endothelial isoform of nitric oxide synthase (eNOS) and angiopoietins. We also propose various pathways that have therapeutic potential in our opinion. Greater in-depth study of VEGF-A and angiopoietins, the state of glomerular VEGF resistance, the relationship of VEGF receptor 2/nephrin, VEGF/insulin receptors/nephrin and the relationship of VEGF/eNOS-NO at glomerular level could provide solutions to the pressing world problem of DN and generate new treatment alternatives (AU)


Subject(s)
Humans , Diabetic Nephropathies/physiopathology , Receptors, Vascular Endothelial Growth Factor/physiology , Receptor, Insulin/physiology , Angiopoietins/physiology , Podocytes/physiology , Insulin Resistance/physiology , Nitric Oxide/physiology , Glomerular Filtration Rate/physiology
16.
Diabetes ; 64(5): 1743-59, 2015 May.
Article in English | MEDLINE | ID: mdl-25475434

ABSTRACT

The onset of diabetic nephropathy (DN) is highlighted by glomerular filtration barrier abnormalities. Identifying pathogenic factors and targetable pathways driving DN is crucial to developing novel therapies and improving the disease outcome. Semaphorin3a (sema3a) is a guidance protein secreted by podocytes. Excess sema3a disrupts the glomerular filtration barrier. Here, using immunohistochemistry, we show increased podocyte SEMA3A in renal biopsies from patients with advanced DN. Using inducible, podocyte-specific Sema3a gain-of-function (Sema3a(+)) mice made diabetic with streptozotocin, we demonstrate that sema3a is pathogenic in DN. Diabetic Sema3a(+) mice develop massive proteinuria, renal insufficiency, and extensive nodular glomerulosclerosis, mimicking advanced DN in humans. In diabetic mice, Sema3a(+) exacerbates laminin and collagen IV accumulation in Kimmelstiel-Wilson-like glomerular nodules and causes diffuse podocyte foot process effacement and F-actin collapse via nephrin, αvß3 integrin, and MICAL1 interactions with plexinA1. MICAL1 knockdown and sema3a inhibition render podocytes not susceptible to sema3a-induced shape changes, indicating that MICAL1 mediates sema3a-induced podocyte F-actin collapse. Moreover, sema3a binding inhibition or podocyte-specific plexinA1 deletion markedly ameliorates albuminuria and abrogates renal insufficiency and the diabetic nodular glomerulosclerosis phenotype of diabetic Sema3a(+) mice. Collectively, these findings indicate that excess sema3a promotes severe diabetic nephropathy and identifies novel potential therapeutic targets for DN.


Subject(s)
Diabetic Nephropathies/metabolism , Podocytes/metabolism , Semaphorin-3A/metabolism , Actins/metabolism , Animals , Chromones , Collagen Type IV/genetics , Collagen Type IV/metabolism , Diabetes Mellitus, Experimental , Diabetic Nephropathies/pathology , Enzyme-Linked Immunosorbent Assay , Gene Expression Regulation , Gene Knockdown Techniques , Humans , Integrin alphaVbeta3/genetics , Integrin alphaVbeta3/metabolism , Laminin/genetics , Laminin/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Microfilament Proteins , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Proteinuria/etiology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Renal Insufficiency , Semaphorin-3A/blood , Semaphorin-3A/genetics , Semaphorin-3A/urine , WT1 Proteins/genetics , WT1 Proteins/metabolism , Xanthones
17.
Am J Kidney Dis ; 65(3): 513-7, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25542409

ABSTRACT

Hyponatremia is an electrolyte abnormality that occurs in infancy due to a variety of inherited and acquired disorders. Infants with hyponatremia can present with neurologic symptoms such as vomiting, weakness, and seizures. Common causes of hyponatremia in the infant population are excess ingestion or administration of hypotonic fluids and excessive gastrointestinal salt loss. Hyponatremia in infancy also can be a sign of less common disorders, such as mineralocorticoid deficiency or resistance, and disregulation of arginine vasopressin with impaired free-water removal. Treatment of infants with hyponatremia is dependent on the severity of symptoms and the cause of hyponatremia. In nephrogenic syndrome of inappropriate antidiuresis (NSIAD), fluid retention is due to a gain-of-function mutation in the arginine vasopressin receptor 2 (AVPR2) gene leading to low arginine vasopressin levels. We describe the case of an infant with hyponatremia due to NSIAD, whose mother also has a known mutation in the AVPR2 gene. We report the approach to the treatment of hyponatremia and its unique challenges in infancy.


Subject(s)
Hyponatremia/diagnosis , Hyponatremia/therapy , Humans , Hyponatremia/blood , Infant , Male , Sodium/blood , Treatment Outcome , Urea/administration & dosage
18.
J Am Soc Nephrol ; 25(8): 1814-24, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24578128

ABSTRACT

VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess podocyte VEGF-A on the renal phenotype of endothelial nitric oxide synthase (eNOS) knockout mice. Podocyte-specific VEGF(164) gain of function in eNOS(-/-) mice resulted in nodular glomerulosclerosis, mesangiolysis, microaneurysms, and arteriolar hyalinosis associated with massive proteinuria and renal failure in the absence of diabetic milieu or hypertension. In contrast, podocyte-specific VEGF(164) gain of function in wild-type mice resulted in less pronounced albuminuria and increased creatinine clearance. Transmission electron microscopy revealed glomerular basement membrane thickening and podocyte effacement in eNOS(-/-) mice with podocyte-specific VEGF(164) gain of function. Furthermore, glomerular nodules overexpressed collagen IV and laminin extensively. Biotin-switch and proximity ligation assays demonstrated that podocyte-specific VEGF(164) gain of function decreased glomerular S-nitrosylation of laminin in eNOS(-/-) mice. In addition, treatment with VEGF-A decreased S-nitrosylated laminin in cultured podocytes. Collectively, these data indicate that excess glomerular VEGF-A and eNOS deficiency is necessary and sufficient to induce Kimmelstiel-Wilson-like nodular glomerulosclerosis in mice through a process that involves deposition of laminin and collagen IV and de-nitrosylation of laminin.


Subject(s)
Diabetic Nephropathies/etiology , Nitric Oxide Synthase Type III/physiology , Podocytes/metabolism , Proteinuria/etiology , Renal Insufficiency/etiology , Vascular Endothelial Growth Factor A/physiology , Animals , Cell Culture Techniques , Collagen Type IV/metabolism , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Glomerular Basement Membrane/metabolism , Glomerular Basement Membrane/pathology , Laminin/metabolism , Mice , Mice, Knockout , Nitric Oxide Synthase Type III/genetics , Proteinuria/metabolism , Proteinuria/pathology , Renal Insufficiency/metabolism , Renal Insufficiency/pathology
19.
Pediatr Nephrol ; 29(4): 751-5, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24464477

ABSTRACT

Semaphorin3a (sema3a), a member of class 3 semaphorins, is a guidance protein that regulates angiogenesis, branching morphogenesis, axon growth, and cell migration, and has pleiotropic roles on organogenesis, immune response, and cancer. Sema3a is secreted by podocytes and is required for normal kidney patterning and glomerular filtration barrier development. We recently discovered that after completion of kidney development, Sema3a gain-of-function in podocytes leads to proteinuric glomerular disease in mice. Excess sema3a causes foot process effacement, glomerular basement lamination, and endothelial damage in vivo, and disrupts cell autonomously podocyte shape by down-regulating nephrin and inhibiting αvß3 integrin. We identified a novel direct interaction between nephrin and plexinA1, the sema3a signaling receptor. Nephrin-plexinA1 interaction links the slit-diaphragm signaling complex to extracellular sema3a signals. Hence, sema3a functions as an extracellular negative regulator of the structure and function of the glomerular filtration barrier.


Subject(s)
Kidney/embryology , Podocytes/metabolism , Podocytes/pathology , Semaphorin-3A/metabolism , Animals , Humans , Kidney Diseases/genetics , Kidney Diseases/metabolism , Kidney Diseases/pathology , Organogenesis , Semaphorin-3A/genetics , Signal Transduction
20.
Clin Nephrol ; 82(3): 205-10, 2014 Sep.
Article in English | MEDLINE | ID: mdl-23391318

ABSTRACT

Chronic kidney disease is common in pediatric patients following hematopoietic stem cell transplant. Its etiology is likely multifactorial and depends both on pre-conditioning regimens as well as immunosuppressive therapy and posttransplant prophylactic medications. Graft vs. host disease (GVHD) is a common sequela of hematopoietic stem cell transplant and has been associated with the nephrotic syndrome (NS). Here we report a case of a pediatric patient who developed proteinuria and renal insufficiency after stem cell transplant. A kidney biopsy showed chronic interstitial nephritis and extensive foot process effacement, which are likely sequelae of GVHD. Moreover we show decreased CD4 and CD3 lymphocyte counts in the interstitial infiltrate, suggesting that abnormal lymphocyte response might play a role in podocyte injury following GVHD. This case illustrates the importance of the kidney biopsy in the assessment of stem cell transplant-mediated renal failure.


Subject(s)
Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Nephritis, Interstitial/etiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/surgery , Proteinuria/etiology , Renal Insufficiency/etiology , Biopsy , Child , Fatal Outcome , Graft vs Host Disease/diagnosis , Humans , Kidney/pathology , Male , Nephritis, Interstitial/diagnosis , Predictive Value of Tests , Proteinuria/diagnosis , Recurrence , Renal Insufficiency/diagnosis
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