RESUMO
BACKGROUND: We report the induction of gremlin, a bone morphogenetic protein antagonist, in cultured human mesangial cells exposed to high glucose and transforming growth factor beta (TGF-beta) levels in vitro and kidneys from diabetic rats in vivo. METHODS: Gremlin expression was assessed in human diabetic nephropathy by means of in situ hybridization, immunohistochemistry, and real-time polymerase chain reaction and correlated with clinical and pathological indices of disease. RESULTS: Gremlin was not expressed in normal human adult kidneys. Conversely, abundant gremlin expression was observed in human diabetic nephropathy. Although some gremlin expression was observed in occasional glomeruli, gremlin expression was most prominent in areas of tubulointerstitial fibrosis, where it colocalized with TGF-beta expression. Gremlin messenger RNA levels correlated directly with renal dysfunction, determined by means of serum creatinine level, but not with proteinuria level. There was a strong correlation between gremlin expression and tubulointerstitial fibrosis score. CONCLUSION: In aggregate, these results indicate that the developmental gene gremlin reemerges in the context of tubulointerstitial fibrosis in diabetic nephropathy and suggests a role for TFG-beta as an inducer of gremlin expression in this context.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Mesângio Glomerular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Fator de Crescimento Transformador beta/fisiologia , Proteínas Morfogenéticas Ósseas/genética , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Citocinas , Nefropatias Diabéticas/patologia , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Mesângio Glomerular/patologia , Glucose/farmacologia , Humanos , Hibridização In Situ , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Renais/metabolismo , Nefrite Intersticial/metabolismo , Proteínas , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta1RESUMO
Progressive renal fibrosis is the end process of renal injury leading to kidney failure. Current therapies for chronic renal failure aim to slow this process but fail to halt its progression. As the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis are unravelled, potential treatments for this growing clinical problem should emerge. Gremlin, a developmental regulator of bone morphogenetic proteins (BMPs), has recently been implicated in processes such as glomerulosclerosis, tubulointerstitial fibrosis and cellular hypertrophy, and may represent a novel therapeutic target in progressive renal diseases.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Nefropatias/etiologia , Animais , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/fisiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/fisiopatologia , Dimerização , Progressão da Doença , Retroalimentação Fisiológica , Fibrose , Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/fisiopatologia , Proteínas Hedgehog , Humanos , Hipertrofia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Nefropatias/fisiopatologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Glomérulos Renais/metabolismo , Camundongos , Camundongos Knockout , Nefrite Intersticial/genética , Nefrite Intersticial/fisiopatologia , Ratos , Transativadores/fisiologiaRESUMO
Nephrogenesis is controlled by a sequence of inductive signals between different areas of the developing kidney. As these signals are being elucidated, it has become clear that many important developmental genes are re-expressed in the mature organ following injury, possibly as part of repair and regeneration. While this reuse of developmental pathways may contribute to healing and repair, it may alternatively result in scar formation if specific components of the pathways are missing, if the temporal correlation of various elements is faulty, or if an injurious stimulus persists. In the review we will use diabetic nephropathy as an example to illustrate this paradigm in renal disease. The pathogenesis of diabetic nephropathy is complex and characterized by altered expression of many genes, including growth factors, apoptotic regulators, cellular matrix components, and cytoskeletal proteins. Many of these factors also function during kidney development. The elucidation of the roles these genes play in nephrogenesis and of their array of molecular partners and modulators may ultimately shed light on the pathogenesis of disease (and indeed vice versa), and may even suggest new therapeutic strategies.
Assuntos
Nefropatias Diabéticas/genética , Animais , Proteína Morfogenética Óssea 7 , Proteínas Morfogenéticas Ósseas/genética , Fator de Crescimento do Tecido Conjuntivo , Fatores de Crescimento Endotelial/genética , Fator de Crescimento Epidérmico/genética , Humanos , Proteínas Imediatamente Precoces/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Rim/embriologia , Linfocinas/genética , Metaloproteinases da Matriz/genética , Proteínas/genética , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
By analysing the expression and function of DN-associated genes during renal development in vivo, it may be possible to shed light on their pathogenic roles in the disease. The embryos of the African clawed frog Xenopus laevis provide a useful model for analysing early embryonic development, particularly organogenesis. Their rapid, external development and the large size of embryos allow for ease of observation and manipulation of the developmental programme. The Xenopus pronephros represents a single nephron, the basic unit of the successive vertebrate renal organs, i.e. the mesonephros and metanephros, and thus provides a useful model of nephrogenesis. Suppression subtractive hybridization was used to identify genes induced when primary cultures of mesangial cells are exposed to high extracellular glucose. Among these genes was the bone morphogenetic protein (BMP) gremlin. Interestingly gremlin is expressed in Xenopus pronephros at stage 27 where it has the potential to interact with BMPs and related regulators of nephrogenesis. Further analysis of the role of gremlin in renal development may shed light on their roles in disease.
