Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy

DeRubertis, Frederick R.; Craven, Patricia A.

doi:10.2337/diabetes.43.1.1

Cited by 245 publications

(94 citation statements)

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“…The fact that expression of both rat munc13-1 and munc13-2 is found to be increased after only 1 d of hyperglycemia suggests that overexpression of these genes is a consequence of hyperglycemia and not secondary to stimulation by DAG. Therefore, in diabetes, there may be two mechanisms acting to increase activity of hmunc13: 1) hyperglycemia itself, and 2) hyperglycemia-induced increase in cellular DAG (Hise and Mehta, 1988;Derubertis and Craven, 1994;King et al, 1997). It is not our intention to provide a critical comparison of in vitro and in vivo manifestation.…”

Section: Discussionmentioning

confidence: 99%

Human munc13 Is a Diacylglycerol Receptor that Induces Apoptosis and May Contribute to Renal Cell Injury in Hyperglycemia

Song

Ailenberg

Silverman

1999

MBoC

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We have previously shown that human munc13 (hmunc13) is up-regulated by hyperglycemia under in vitro conditions in human mesangial cell cultures. The purpose of the present study was to determine the cellular function of hmunc13. To do this, we have investigated the subcellular localization of hmunc13 in a transiently transfected renal cell line, opossum kidney cells. We have found that hmunc13 is a cytoplasmic protein and is translocated to the Golgi apparatus after phorbol ester stimulation. In addition, cells transfected with hmunc13 demonstrate apoptosis after treatment with phorbol ester, but cells transfected with an hmunc13 deletion mutant in which the diacylglycerol (C1) binding domain is absent exhibit no change in intracellular distribution and no induction of apoptosis in the presence of phorbol ester stimulation. We conclude that both the diacylglycerol-induced translocation and the apoptosis represent functional activity of hmunc13. We have also demonstrated that munc13-1 and munc13-2 are localized mainly to cortical epithelial cells in rat kidney and both are overexpressed under conditions of hyperglycemia in a streptozotocin-treated diabetic rat model. Taken together, our data suggest that hmunc13 serves as a diacylglycerol-activated, PKC-independent signaling pathway capable of inducing apoptosis and that this pathway may contribute to the renal cell complications of hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

Human munc13 Is a Diacylglycerol Receptor that Induces Apoptosis and May Contribute to Renal Cell Injury in Hyperglycemia

Song

Ailenberg

Silverman

1999

MBoC

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“…O aumento da PKC relaciona-se aos níveis celulares aumentados de diacilglicerol, maior modulador endógeno das vias glicolíticas da metabolização da glicose. Em conjunto, estas observações sugerem que o prejuízo da formação do GMPc, mediado pela redução do óxido nítrico, em resposta ao aumento da PKC em ambiente rico em glicose, pode representar uma importante via pela qual a toxicidade da glicose é traduzida em aumento da susceptibilidade celular no diabetes (73).…”

Section: Lagranha Et Alunclassified

Bases moleculares da glomerulopatia diabética

Lagranha¹,

Fiorino²,

Casarini

et al. 2007

Arq Bras Endocrinol Metab

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RESUMOO principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-β1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-β1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes -e aditivos -na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional. ABSTRACT Molecular Bases of Diabetic Nephropathy.The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra-and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-β1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-β1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of d...

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“…Nevertheless hyperglycemia increases diacylglycerol, a strong activator of PKC (Lee et al, 1989, Ishii et al 1998 chronically activated in diabetic tissues (Inoguchi et al, 1992;deRubertis and Craven, 1994). The promoter region of human eNOS gene contains a phorbol ester responsive element (Marsden et al, 1993), suggesting that PKC activation induces eNOS mRNA expression.…”

Section: Introductionmentioning

confidence: 99%