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1.
Kidney Int ; 89(6): 1307-23, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27181777

RESUMO

Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.


Assuntos
Senescência Celular/genética , Cistos/genética , Células Epiteliais/fisiologia , Doenças Renais Císticas/genética , Túbulos Renais/fisiologia , Cinesinas/genética , Fatores de Transcrição Kruppel-Like/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Pontos de Checagem do Ciclo Celular/genética , Quinase 1 do Ponto de Checagem/metabolismo , Cílios/patologia , Dano ao DNA/genética , Modelos Animais de Doenças , Células Epiteliais/citologia , Fibrose , Citometria de Fluxo , Imunofluorescência , Humanos , Imidazóis/farmacologia , Túbulos Renais/citologia , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Fenótipo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Proteína Supressora de Tumor p53/metabolismo
2.
Am J Physiol Renal Physiol ; 310(9): F895-908, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26887830

RESUMO

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531-536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377-384, 2013). DGKε is unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2 are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2 supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.


Assuntos
Ciclo-Oxigenase 2/biossíntese , Diacilglicerol Quinase/genética , Dinoprostona/biossíntese , Endotélio/patologia , Glomerulonefrite/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Envelhecimento/patologia , Animais , Movimento Celular , Glomerulonefrite/enzimologia , Glomerulonefrite/metabolismo , Testes de Função Renal , Glomérulos Renais/enzimologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica , Cicatrização
3.
Am J Physiol Renal Physiol ; 309(9): F770-8, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26290370

RESUMO

Hedgehog (Hh) is an evolutionary conserved signaling pathway that has important functions in kidney morphogenesis and adult organ maintenance. Recent work has shown that Hh signaling is reactivated in the kidney after injury and is an important mediator of progressive fibrosis. Pericytes and fibroblasts have been proposed to be the principal cells that respond to Hh ligands, and pharmacological attenuation of Hh signaling has been considered as a possible treatment for fibrosis, but the effect of Hh inhibition on tubular epithelial cells after kidney injury has not been reported. Using genetically modified mice in which tubule-derived hedgehog signaling is increased and mice in which this pathway is conditionally suppressed in pericytes that express the proteoglycan neuron glial protein 2 (NG2), we found that suppression of Hh signaling is associated with decreased macrophage infiltration and tubular proliferation but also increased tubular apoptosis, an effect that correlated with the reduction of tubular ß-catenin activity. Collectively, our data suggest a complex function of hedgehog signaling after kidney injury in initiating both reparative and proproliferative, prosurvival processes.


Assuntos
Injúria Renal Aguda/etiologia , Proteínas Hedgehog/metabolismo , Túbulos Renais/metabolismo , Transdução de Sinais , Obstrução Ureteral/complicações , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Antígenos/metabolismo , Apoptose , Proliferação de Células , Sobrevivência Celular , Modelos Animais de Doenças , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Pericitos/metabolismo , Pericitos/patologia , Proteoglicanas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened , Alcaloides de Veratrum/farmacologia , Proteína GLI1 em Dedos de Zinco , beta Catenina/metabolismo
4.
Hum Mol Genet ; 20(21): 4155-66, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21816948

RESUMO

Hedgehog (Hh) is a core signaling pathway implicated in fundamental processes during embryonic kidney development. We previously found that loss-of-function mutations in the transcription factor GLIS2, a putative vertebrate ortholog of Drosophila Ci, cause nephronophthisis type 7 in humans and mice. Kidney tubular cells in Glis2-knockout mice acquire mesenchymal phenotype, but the cellular mechanisms of this transition are unknown. Here, we demonstrate that Glis2 is a functional component of Hh signaling and is necessary to suppress this pathway in the postnatal kidney. In the epithelial compartment, Glis2 opposes Gli1 activity by binding cis-acting regulatory sequences in the 5' flanking regions of Snai1 and Wnt4, thereby inhibiting de-differentiation of tubular cells. We conclude that Glis2 is necessary to inhibit Hh signaling and to maintain the mature tubular epithelial phenotype in the adult kidney. This is the first description of a molecular mechanism that links the Hh signaling pathway to cystic kidney diseases and can open new avenues for the treatment of diverse ciliopathies.


Assuntos
Proteínas Hedgehog/metabolismo , Néfrons/crescimento & desenvolvimento , Néfrons/metabolismo , Transdução de Sinais , Animais , Animais Recém-Nascidos , Diferenciação Celular/genética , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Proteínas Hedgehog/genética , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Néfrons/patologia , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição PAX2/metabolismo , Fenótipo , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Wnt4/genética , Proteína Wnt4/metabolismo , Proteína GLI1 em Dedos de Zinco
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