RESUMO
Mutations in the TRPC6 calcium channel (Transient receptor potential channel 6) gene have been associated with familiar forms of Focal and Segmental Glomerulosclerosis (FSGS) affecting children and adults. In addition, acquired glomerular diseases are associated with increased expression levels of TRPC6. However, the exact role of TRPC6 in the pathogenesis of FSGS remains to be elucidated. In this work we describe the generation and phenotypic characterization of three different transgenic mouse lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K) previously related to FSGS. Consistent with the human phenotype a non-nephrotic range of albuminuria was detectable in almost all transgenic lines. The histological analysis demonstrated that the transgenic mice developed a kidney disease similar to human FSGS. Differences of 2-3 folds in the presence of glomerular lesions were found between the non transgenic and transgenic mice expressing Trpc6 in its wild type or mutant forms specifically in podocytes. Electron microscopy of glomerulus from transgenic mice showed extensive podocyte foot process effacement. We conclude that overexpression of Trpc6 (wild type or mutated) in podocytes is sufficient to cause a kidney disease consistent with FSGS. Our results contribute to reinforce the central role of podocytes in the etiology of FSGS. These mice constitute an important new model in which to study future therapies and outcomes of this complex disease.
Assuntos
Expressão Gênica , Glomerulosclerose Segmentar e Focal/metabolismo , Podócitos/metabolismo , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Glomerulosclerose Segmentar e Focal/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Mutação , Especificidade de Órgãos , Canal de Cátion TRPC6RESUMO
A case of two young adult brothers with nephrotic syndrome secondary to focal segmental glomerulosclerosis is reported. Steroid resistance prompted us to perform genetic studies. These showed a compound heterozygous mutation of NPHS2, the gene encoding podocin. It was composed of a missense mutation in exon 7 (A284V) and the non-neutral polymorphism R229Q in exon 5. We review literature supporting the genetic basis of the disease.
Assuntos
Heterozigoto , Proteínas de Membrana/genética , Mutação , Síndrome Nefrótica/genética , Adulto , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Rim/patologia , Masculino , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologiaRESUMO
The importance of tubulointerstitial injury in the pathophysiology of human essential hypertension, and particularly salt sensitivity, is increasingly recognized. Since the renal kallikrein-kinin system (KKS) is located in the tubulointerstitial region of the kidney it is reasonable to expect that injury to this area, whatever the cause, may impair KKS production and compromise its role in blood pressure regulation. In this review we discuss evidence of injury in the renal kallikrein-producing structures in three different experimental models characterized by prominent tubulointerstitial lesions: subtotal nephrectomy; inhibition of nitric oxide synthase; and overload proteinuria. These three experimental models have in common the development of important tubulointerstitial damage and salt-sensitive hypertension expressed after the initial injury has ceased. In these three models, reduced KKS activity may contribute to the establishment of a pathophysiologic state characterized by unopposed hyperactivity of the renin-angiotensin system, resulting in salt retention.
Assuntos
Hipertensão/etiologia , Hipertensão/fisiopatologia , Sistema Calicreína-Cinina , Rim/metabolismo , Cloreto de Sódio/farmacologia , Animais , Inibidores Enzimáticos/farmacologia , Rim/patologia , NG-Nitroarginina Metil Éster/farmacologia , Nefrectomia/métodos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Proteinúria/complicações , Proteinúria/metabolismo , Proteinúria/patologiaRESUMO
BACKGROUND: The molecular mechanisms of renal injury and fibrosis in proteinuric nephropathies are not completely elucidated but the renin-angiotensin system (RAS) is involved. Idiopathic membranous nephropathy (MN), a proteinuric disease, may progress to renal failure. Our aim was to investigate the localization of RAS components in MN and their correlation with profibrotic parameters and renal injury. METHODS: Renal biopsies from 20 patients with MN (11 with progressive disease) were studied for the expression of RAS components [angiotensin-converting enzyme (ACE) and angiotensin II (Ang II)] by immunohistochemistry. Transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF)-BB were studied by by in situ hybridization, and myofibroblast transdifferentiation by alpha-smooth muscle actin (alpha-SMA) staining. RESULTS: ACE immunostaining was elevated in tubular cells and appeared in interstitial cells colocalized in alpha-actin-positive cells in progressive disease. Elevated levels of Ang II were observed in tubules and infiltrating interstitial cells. TGF-beta and PDGF mRNAs were up-regulated mainly in cortical tubular epithelial cells in progressive disease (P < 0.01) and correlated with the myofibroblast transdifferentiation (r = 0.8, P < 0.01 for TGF-beta; r = 0.6, P < 0.01 for PDGF). Moreover, in serial sections of progressive cases, the ACE and Ang II over-expression was associated with the tubular expression of these pro-fibrogenic factors, and with the interstitial infiltration and myofibroblast activation. CONCLUSION: Intrarenal RAS is selectively activated in progressive MN. De novo expression of ACE at sites of tubulointerstitial injury suggests that the in situ Ang II generation could participate in tubular TGF-beta up-regulation, epithelial-myofibroblast transdifferentiation, and disease progression. These results suggest a novel role of Ang II in human tubulointerstitial injury.