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1.
Invest Ophthalmol Vis Sci ; 61(2): 5, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031577

RESUMO

Purpose: To investigate characteristics of the foveal pit and the foveal avascular zone (FAZ) in patients with Alport syndrome (AS), a rare monogenetic disease due to mutations in genes encoding for collagen type IV. Methods: Twenty-eight eyes of nine patients with AS, and five autosomal-recessive carriers and 15 eyes from 15 age-similar healthy control subjects were examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Foveal configuration and FAZ measures including the FAZ area, circularity, and vessel density in the central 1° and 3° were correlated. Results: Foveal hypoplasia was found in 10 eyes from seven patients with either genotype. In contrast, a staircase foveopathy was found in seven eyes of four X-linked AS patients. The average FAZ area did not differ significantly between AS patients and control subjects (mean ± SD 0.24 ± 0.24 mm2 vs. 0.21 ± 0.09 mm2; P = 0.64). Five eyes showed absence or severe anomalies of the FAZ with crossing macular capillaries that was linked to the degree of foveal hypoplasia on OCT images leading to a significant inverse correlation of FAZ area and foveal thickness (r = -0.88; P < 0.001). In contrary, female patients with X-linked mutations exhibited a significantly greater FAZ area (0.48 ± 0.30 mm2 vs. 0.21 ± 0.09 mm2; P = 0.007), in line with OCT findings of a staircase foveopathy. Conclusions: The foveal phenotypic spectrum in AS ranges from foveal hypoplasia and absence of a FAZ to staircase foveopathy with an enlarged FAZ. Because the development of the FAZ and foveal pit are closely related, these findings suggest an important role for collagen type IV in foveal development and maturation.


Assuntos
Fóvea Central/anormalidades , Nefrite Hereditária/patologia , Doenças Retinianas/patologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Colágeno Tipo IV/genética , Estudos Transversais , Feminino , Angiofluoresceinografia , Fóvea Central/crescimento & desenvolvimento , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nefrite Hereditária/genética , Nefrite Hereditária/fisiopatologia , Fenótipo , Estudos Prospectivos , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Vasos Retinianos/patologia , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
2.
Clin Sci (Lond) ; 134(4): 379-388, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32064497

RESUMO

Alport syndrome is a rare genetic disease that results in disordered basement membrane type IV collagen resulting in occular and auditory defects as well of progressive kidney disease. Although no 'cure' currently exists, therapeutic blockade of the renin-angiotensin-aldosterone system can slow the progression to end-stage kidney disease (ESKD). Clinical trials for treatments in preventing chronic kidney disease have largely been negative over the last two decades until recent trials have shown positive cardiovascular and renal outcomes of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with diabetes mellitus. Although marketed as medications for Type 2 diabetes, SGLT2 inhibitors have been found to have additional properties that are nephroprotective which makes them a potential candidate for treatment for those with other forms of progressive kidney disease. This review discusses the evidence for the use of SGLT2 inhibitors as a potential treatment in Alport syndrome that may slow the progression of chronic kidney disease and prevent patients reaching ESKD.


Assuntos
Nefrite Hereditária/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Nefrite Hereditária/fisiopatologia , Substâncias Protetoras/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
3.
Croat Med J ; 60(5): 458-462, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31686460

RESUMO

Alport syndrome (AS) is a genetically heterogenic, structural disorder of the glomerular basement membrane (GBM) due to the mutation of COL4A3, COL4A4, or COL4A5 genes, which clinically presents as progressive hematuric nephritis with ultrastructural changes of the GBM, high tone sensorineural hearing loss, and ocular lesions. About 15% of AS cases have autosomal mutations of COL4A3 and COL4A4 genes, including homozygous and compound heterozygous mutations. Here, we present a case of a two-year-old boy with autosomal recessive Alport syndrome (ARAS) caused by a novel c.193-2A>C COL4A4 mutation. The patient had a delayed motor and sensory development coupled with speech and language delay, megalencephaly, hematuria and proteinuria, and normal tonal audiogram and ophthalmology exam. Extensive genetic, metabolic, and neurologic workup performed at the age of 10 months was unremarkable and patient's megalencephaly was described as familial benign megalencephaly. Kidney biopsy analysis showed characteristic signs of AS. Mutations screening with use of Illumina MiSeq platform revealed that the patient was homozygous for a newly discovered splice acceptor pathogenic variant c.193-2A>C found in COL4A4 at the genomic position chr2:227985866 and both parents were heterozygous carriers. The genetic heterogeneity of AS makes the diagnostic process challenging. Although renal biopsy provides information about the characteristic GBM changes and the degree of renal parenchyma damage (interstitial fibrosis and tubular atrophy ratio), genetic testing is a more sensitive and specific method that also gives insight into potential disease severity and clinical course, and provides the basis for genetic counseling.


Assuntos
Colágeno Tipo IV/genética , Pré-Escolar , Humanos , Masculino , Mutação/genética , Nefrite Hereditária/genética
4.
J Biol Regul Homeost Agents ; 33(5 Suppl. 1): 19-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31630709

RESUMO

Alport's syndrome (AS, OMIM 301050) is a hereditary disorder characterized by progressive renal failure, hearing impairment and ocular changes. It is clinically and genetically heterogeneous and in its natural history, renal disease progresses from microscopic haematuria to proteinuria, and finally to progressive renal insufficiency. AS is caused by an inherited defect in a type IV collagen, a structural material, expressed in many tissues that is essential for the normal function of different parts of the body. In most of cases, about the 85%, Alport's syndrome is X-linked and is originated by mutations in the COL4A5 gene. In the remaining cases, it may be inherited in either an autosomal recessive, or rarely in an autosomal dominant manner. Mostly, the condition is caused by mutations in the COL4A3 or COL4A4 genes. Coexisting mutations in COL4A3, COL4A4, COL4A5 or COL4A6 were found to cause an Alport's syndrome phenotype with digenic inheritance. Diagnosis of the condition is based on family history, clinical signs, and specific procedures such as a kidney biopsy. The diagnosis can be confirmed by genetic testing. Treatment may include use of a hearing aid, hemodialysis, and peritoneal dialysis to treat those with end-stage renal failure, and, as the last step, kidney transplantation. Firstly described by Arthur C. Alport's, in 1927, over the years it has become a pathology of high scientific interest. At the moment, thanks to advances in diagnostic techniques, it is possible to make an early diagnosis avoiding irreversible damages and life -threatening complications.


Assuntos
Colágeno Tipo IV/genética , Nefrite Hereditária/genética , Humanos , Falência Renal Crônica , Mutação , Fenótipo
5.
Medicine (Baltimore) ; 98(39): e17054, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574802

RESUMO

RATIONALE: To report the visual status and results of phacoemulsification cataract surgery in a young patient with Alport syndrome associated with bilateral anterior lenticonus. The milestone of this report is the use of anterior segment optical coherence tomography (AS-OCT) to confirm the central protrusion of the anterior surface of the crystalline lens. PATIENT CONCERNS: A 23-year-old young woman presented with severe progressive visual loss in both eyes, which started several years ago. DIAGNOSES: Refractive status was indicative of high myopia with astigmatism and vision was not improved with optimal correction to better than 0.1 in the right eye and 0.2 in the left eye (visual acuities given in decimal notation). Slit-lamp examination showed transparent cornea, anterior lenticonus and posterior sub-capsular cataract in both eyes. The classical appearance of oil droplet was evident using retro-illumination on the slit lamp. INTERVENTIONS: The natural lenses were replaced with intraocular lens (IOL). OUTCOMES: An excellent refractive status achieved associated with an uncorrected distance visual acuity 0.9 and 0.8 in the right and left eye, respectively. LESSONS: AS-OCT is a valuable device for confirming the budging of the anterior crystalline lens surface.


Assuntos
Cápsula do Cristalino/patologia , Cápsula do Cristalino/cirurgia , Córtex do Cristalino/patologia , Córtex do Cristalino/cirurgia , Nefrite Hereditária/patologia , Nefrite Hereditária/cirurgia , Facoemulsificação , Feminino , Humanos , Cápsula do Cristalino/diagnóstico por imagem , Córtex do Cristalino/diagnóstico por imagem , Nefrite Hereditária/diagnóstico por imagem , Tomografia de Coerência Óptica , Baixa Visão/diagnóstico por imagem , Baixa Visão/etiologia , Baixa Visão/cirurgia , Adulto Jovem
6.
Zhonghua Er Ke Za Zhi ; 57(9): 674-679, 2019 Sep 02.
Artigo em Chinês | MEDLINE | ID: mdl-31530352

RESUMO

Objective: To examine genetic variants of familial hematuria (FH) associated genes in 3 families with hematuria with probands initially diagnosed with IgA nephropathy (IgAN). Methods: A retrospective analysis was performed on the clinical data, laboratory tests and genetic test results of three children with hematuria and the probands in three families with hematuria. The families were ascertained at the Department of Pediatrics, Fuzhou General Hospital of Nanjing Military Command from August 2014 to May 2018. Results: The proband of Family One, an 8-year-old boy, manifested gross hematuria. His renal biopsy pathology revealed IgAN. His father also manifested hematuria. Genetic testing showed that the proband and his father carried a heterozygous variant of the CFHR5 gene,533A>G (Asn178Ser). The child of Family Two, a 4-year-old girl, manifested hematuria. Her father, the proband of the family, was 36 years old, and manifested hematuria, proteinuria, high-frequency sensorineural deafness and renal insufficiency. He was diagnosed as IgAN according to clinical manifestations, renal pathology and routine immunohistochemistry without renal biopsy electron microscopy, renal tissue type Ⅳ collagen α3, α4, α5 chains immunofluorescence and skin type Ⅳ collagen α5 chain immunofluorescence. Genetic testing showed that the girl carried a heterozygous variant of the COL4A5 gene,566G>T (Gly189Val), and her father carried the hemizygous variant. The child of Family Three, a 7-year-old girl, manifested hematuria and proteinuria. Her mother, the proband of the family, was 34 years old, and manifested hematuria and proteinuria as well. The proband was diagnosed as IgAN by the same method used for Family Two. The girl's grandfather died of uremia at the age of 44. Genetic testing showed that the girl and her mother carried a heterozygous variant 539G>A (Gly180Glu)in COL4A5 gene. Conclusions: The variant of the CFHR5 gene identified in Family One is of uncertain signifance, and the two variants of the COL4A5 gene identified in Families Two and Three are pathogenic. The probands of Families Two and Three are diagnosed as Alport syndrome. The study suggests that clinicians should examine genetic variants of FH associated genes in families with hematuria when the probands were diagnosed as IgAN by their clinical manifestations, renal pathology and routine immunohistochemistry.


Assuntos
Variação Genética/genética , Hematúria/diagnóstico , Nefrite Hereditária/diagnóstico , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos/métodos , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Hematúria/genética , Humanos , Rim , Masculino , Nefrite Hereditária/genética , Estudos Retrospectivos , Sequenciamento Completo do Exoma
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 914-917, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515789

RESUMO

OBJECTIVE: To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase. METHODS: Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product. RESULTS: High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c.4550T>G in exon 47 (inherited from his mother) and c.199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother. CONCLUSION: The compound heterozygous c.4550T>G and c.199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.


Assuntos
Colágeno Tipo IV/genética , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Criança , Éxons , Feminino , Humanos , Masculino , Mutação , Linhagem , Sequenciamento Completo do Exoma
9.
BMJ Case Rep ; 12(8)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31420426

RESUMO

Alport syndrome (AS) is a hereditary disease with various modes of inheritance, X-linked being the the most common. Anterior lenticonus is the characteristic abnormality along with perimacular and peripheral fleck retinopathy. Our two cases of AS had simultaneous anterior and posterior lenticonus with severe temporal macular thinning on optical coherence tomography with no specific renal symptomatology and were diagnosed as AS without any invasive renal biopsy. First patient was a 19-year-old man who presented with compound myopia due to bilateral anterior and posterior lenticonus with perimacular fleck retinopathy and lozenge sign and bilateral moderate sensorineural hearing loss (SNHL). Second patient was a 24-year-old man who presented with difficulty in vision due to bilateral anterior and posterior lenticonus with bilateral severe SNHL. Our cases emphasise the crucial role of an ophthalmologist in diagnosing AS before the onset of renal symptoms and prompting further nephrological work-up in the patient or the carrier.


Assuntos
Doenças do Cristalino/genética , Cristalino/anormalidades , Macula Lutea/anormalidades , Nefrite Hereditária/complicações , Doenças Retinianas/genética , Humanos , Masculino , Adulto Jovem
11.
Saudi J Kidney Dis Transpl ; 30(4): 969-973, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464257

RESUMO

Metachondromatosis is a rare disorder of autosomal inheritance with incomplete penetrance, which is characterized by formation of osteochondroma and enchondroma, caused by loss of function of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene. Diagnosis is made based on the distribution and orientation of lesions with history of regression of lesions with time and confirmed by genetic mutation of PTPN11 gene. We report a rare case of a 24-year-old male with Alport's syndrome with metachondromatosis due to missense variation in PTPN11 gene.


Assuntos
Neoplasias Ósseas/genética , Condromatose/genética , Colágeno Tipo IV/genética , Exostose Múltipla Hereditária/genética , Mutação , Nefrite Hereditária/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Sítios de Splice de RNA , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/enzimologia , Condromatose/diagnóstico , Condromatose/enzimologia , Análise Mutacional de DNA , Exostose Múltipla Hereditária/diagnóstico , Exostose Múltipla Hereditária/enzimologia , Predisposição Genética para Doença , Hemizigoto , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Nefrite Hereditária/diagnóstico , Fenótipo , Fatores de Risco , Adulto Jovem
12.
Nat Commun ; 10(1): 3656, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409793

RESUMO

In this work we model the glomerular filtration barrier, the structure responsible for filtering the blood and preventing the loss of proteins, using human podocytes and glomerular endothelial cells seeded into microfluidic chips. In long-term cultures, cells maintain their morphology, form capillary-like structures and express slit diaphragm proteins. This system recapitulates functions and structure of the glomerulus, including permselectivity. When exposed to sera from patients with anti-podocyte autoantibodies, the chips show albuminuria proportional to patients' proteinuria, phenomenon not observed with sera from healthy controls or individuals with primary podocyte defects. We also show its applicability for renal disease modeling and drug testing. A total of 2000 independent chips were analyzed, supporting high reproducibility and validation of the system for high-throughput screening of therapeutic compounds. The study of the patho-physiology of the glomerulus and identification of therapeutic targets are also feasible using this chip.


Assuntos
Glomérulos Renais/metabolismo , Dispositivos Lab-On-A-Chip , Nefrite Hereditária/metabolismo , Albuminas/metabolismo , Albuminúria/tratamento farmacológico , Albuminúria/metabolismo , Células Imobilizadas/química , Células Imobilizadas/metabolismo , Células Endoteliais/química , Células Endoteliais/metabolismo , Humanos , Glomérulos Renais/química , Glomérulos Renais/efeitos dos fármacos , Masculino , Nefrite Hereditária/tratamento farmacológico , Podócitos/química , Podócitos/metabolismo
13.
Int J Mol Sci ; 20(15)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390839

RESUMO

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor ß (TGFß) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3-/- mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3-/- mice by olmesartan treatment. Upregulation of TGFß and activation of its downstream in Col4a3-/- mice were attenuated by olmesartan in Col4a3-/- mice. Intriguingly, TGFß expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3-/- mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3-/- mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFß-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFß feedback loop to counterbalance intrarenal RAS activation.


Assuntos
Anti-Hipertensivos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Tetrazóis/farmacologia , Fator de Crescimento Transformador beta/genética , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Biópsia , Modelos Animais de Doenças , Fibrose , Túbulos Renais/patologia , Camundongos , Camundongos Knockout , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Proteínas ras/genética , Proteínas ras/metabolismo
14.
Rev Med Chil ; 147(4): 522-526, 2019 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-31344217

RESUMO

Alport syndrome is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. We report two men with Alport syndrome. Both had chronic kidney disease and consulted for long-term loss of visual acuity. One had auditory abnormalities. On the ophthalmological examination, both had anterior lenticonus and one had dot or fleck retinopathy. Those findings are described in up to 50% and 70% of men with X-linked Alport syndrome, respectively. Both patients had a family history of Alport syndrome or suggestive signs and symptoms.


Assuntos
Oftalmopatias/patologia , Nefrite Hereditária/patologia , Adulto , Oftalmopatias/diagnóstico , Oftalmopatias/fisiopatologia , Perda Auditiva Neurossensorial , Humanos , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/fisiopatologia , Retina/patologia , Tomografia de Coerência Óptica , Tonometria Ocular , Acuidade Visual
15.
BMJ Case Rep ; 12(7)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308192

RESUMO

Alport syndrome (AS) is an inherited kidney disease that may lead to end-stage renal disease in early adult life. It is a clinically and genetically heterogeneous nephropathy. The possibility of a patient with haematuria or proteinuria being diagnosed as having AS cannot be excluded even if the patient is female or if the family history is unknown. We report a 3-year-old girl with a de novo frameshift mutation, c.3906delA p.(Gly1303Aspfs*17), in the COL4A5 gene. The significance of the electron microscopic study on the glomerular basement membrane must be emphasised because it is the first step towards the diagnosis of AS. Genetic analysis provides the only conclusive diagnosis of AS, by determining the mode of inheritance and prognosis.


Assuntos
Colágeno Tipo IV/genética , Mutação da Fase de Leitura/genética , Nefrite Hereditária/diagnóstico , Pré-Escolar , Feminino , Membrana Basal Glomerular/ultraestrutura , Hematúria/genética , Heterozigoto , Humanos , Microscopia Eletrônica , Nefrite Hereditária/genética , Proteinúria/genética
17.
Nephrol Dial Transplant ; 34(8): 1272-1279, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31190059

RESUMO

Alport syndrome (AS) is the most frequent inherited kidney disease after autosomal dominant polycystic kidney disease. It has three different patterns of inheritance-autosomal dominant, autosomal recessive and X-linked-which in part explains the wide spectrum of disease, ranging from isolated microhaematuria to end-stage renal disease early in life. The search for a treatment for AS is being pursued vigorously, not only because of the obvious unmet need but also because AS is a rare disease and any drug approved will have an orphan drug designation with its various benefits. Moreover, AS patients are quite young with very few comorbidities, which facilitates clinical trials. This review identifies the particularities of each pattern of inheritance but focuses mainly on new drugs or therapeutic targets for the disease. Most treatment-related investigations are directed not at the main abnormality in AS, namely collagen IV composition, but rather at the associated inflammation and fibrosis. Thus, AS may serve as a proof of concept for numerous drugs of potential value in many diseases that cause chronic kidney disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Nefrite Hereditária/terapia , Preparações Farmacêuticas/administração & dosagem , Transplante de Células-Tronco/métodos , Fibrose/prevenção & controle , Predisposição Genética para Doença , Humanos , Inflamação/prevenção & controle , Nefrite Hereditária/genética , Nefrite Hereditária/patologia
18.
J Am Coll Cardiol ; 73(21): 2705-2718, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31146816

RESUMO

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. OBJECTIVES: The purpose of this study was to identify potential OPN targets in biopsies of HF patients, healthy control subjects, and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), and to characterize the cardiac phenotype of Col4a3-/- mice, relate this to HFpEF, and investigate possible causative roles for OPN in driving the cardiomyopathy. METHODS: OGDHL mRNA and protein were quantified in myocardial samples from patients with HFpEF, heart failure with reduced ejection fraction, and donor control subjects. OGDHL expression was quantified in hiPS-CMs treated with or without anti-OPN antibody. Cardiac parameters were evaluated in Col4a3-/- mice with and without global OPN knockout or AAV9-mediated delivery of 2-oxoglutarate dehydrogenase-like (Ogdhl) to the heart. RESULTS: OGDHL mRNA and protein displayed abnormal abundances in cardiac biopsies of HFpEF (n = 17) compared with donor control subjects (n = 12; p < 0.01) or heart failure with reduced ejection fraction patients (n = 12; p < 0.05). Blockade of OPN in hiPS-CMs conferred increased OGDHL expression. Col4a3-/- mice demonstrated cardiomyopathy with similarities to HFpEF, including diastolic dysfunction, cardiac hypertrophy and fibrosis, pulmonary edema, and impaired mitochondrial function. The cardiomyopathy was ameliorated by Opn-/- coincident with improved renal function and increased expression of Ogdhl. Heart-specific overexpression of Ogdhl in Col4a3-/- mice also improved cardiac function and cardiomyocyte energy state. CONCLUSIONS: Col4a3-/- mice present a model of HFpEF secondary to CKD wherein OPN and OGDHL are intermediates, and possibly therapeutic targets.


Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca Diastólica/etiologia , Complexo Cetoglutarato Desidrogenase/metabolismo , Osteopontina/metabolismo , Disfunção Ventricular Esquerda/etiologia , Animais , Autoantígenos/genética , Colágeno Tipo IV/genética , Fibrose , Terapia Genética , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/patologia , Insuficiência Cardíaca Diastólica/terapia , Complexo Cetoglutarato Desidrogenase/genética , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Nefrite Hereditária/complicações , Osteopontina/genética , Estresse Oxidativo , Disfunção Ventricular Esquerda/metabolismo
19.
Lipids ; 54(6-7): 411-418, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31197846

RESUMO

Alport syndrome is caused by mutations in collagen IV that alter the morphology of renal glomerular basement membrane. Mutations result in proteinuria, tubulointerstitial fibrosis, and renal failure but the pathogenic mechanisms are not fully understood. Using imaging mass spectrometry, we aimed to determine whether the spatial and/or temporal patterns of renal lipids are perturbed during the development of Alport syndrome in the mouse model. Our results show that most sulfatides are present at similar levels in both the wild-type (WT) and the Alport kidneys, with the exception of two specific sulfatide species, SulfoHex-Cer(d18:2/24:0) and SulfoHex-Cer(d18:2/16:0). In the Alport but not in WT kidneys, the levels of these species mirror the previously described abnormal laminin expression in Alport syndrome. The presence of these sulfatides in renal tubules but not in glomeruli suggests that this specific aberrant lipid pattern may be related to the development of tubulointerstitial fibrosis in Alport disease.


Assuntos
Modelos Animais de Doenças , Túbulos Renais/metabolismo , Nefrite Hereditária/metabolismo , Sulfoglicoesfingolipídeos/metabolismo , Animais , Túbulos Renais/patologia , Metabolismo dos Lipídeos , Camundongos , Nefrite Hereditária/patologia
20.
Clin Nephrol ; 92(2): 98-102, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31198170

RESUMO

COL4A5 gene mutations are known as the cause of Alport syndrome (AS), which typically manifests with hematuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities. Here we report a case of a 20-year-old male patient presenting with nephrotic syndrome who was diagnosed as having AS with focal segmental glomerulosclerosis (FSGS) lesion after the renal biopsy was performed. In this patient, the link between AS and FSGS lesion is complicated. Whole-exome sequencing was performed to identify its causal genetic variants, and the results revealed that AS with FSGS lesion is caused by mutation of the COL4A5 gene. COL4A5 gene mutations have phenotypic heterogeneity and thus, we suggest that genetic testing should be considered in such patients for accurate diagnosis and appropriate treatment.


Assuntos
Colágeno Tipo IV/genética , Glomerulosclerose Segmentar e Focal/genética , Mutação/genética , Nefrite Hereditária/genética , Testes Genéticos , Glomerulosclerose Segmentar e Focal/patologia , Hematúria/etiologia , Humanos , Masculino , Nefrite Hereditária/complicações , Nefrite Hereditária/patologia , Adulto Jovem
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