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Altered Protein Kinase C Activation Associated with Rat Embryonic Dysmorphogenesis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratology)
2004 (English)In: Pediatric Research, ISSN 0031-3998, Vol. 56, no 6, 849-857 p.Article in journal (Refereed) Published
Abstract [en]

It has been suggested that protein kinase C (PKC) is involved in the etiology of diabetic complications. The aim of the present study was to investigate the putative involvement of different PKC isoforms (alpha, beta1, beta 2, gamma, delta, epsilon, and zeta) in the embryopathy of diabetic rat pregnancy. Embryos were collected from normal and diabetic rats and assayed for PKC activity, PKC mRNA levels, and PKC protein distribution on gestational d 10 and 11. Embryos of diabetic rats showed markers of increased activity of PKC-alpha, PKC-beta1, PKC-gamma, PKC-delta, and PKC-zeta compared with embryos of normal rats on d 10. In addition, the malformed embryos had further increased PKC-gamma, and PKC-delta activity markers compared with nonmalformed embryos of diabetic rats on gestational d 10. In contrast, maternal diabetes caused only two alterations in PKC activity markers on gestational d 11, i.e. both PKC-alpha and PKC-zeta were decreased in embryos of diabetic rats. We found increased mRNA levels of PKC-beta 1 and PKC-zeta on d 10 in embryos of diabetic rats and decreased mRNA levels of PKC-gamma on d 11 in embryos of diabetic rats. Malformed embryos from diabetic rats showed increased distribution of PKC-beta 1 and PKC-beta 2 protein in the tissue compared with nonmalformed embryos from diabetic rats and embryos from normal rats. We conclude that diabetic rat embryopathy may be associated with increased activity and enhanced tissue distribution of several PKC isoforms in early organogenesis.

Place, publisher, year, edition, pages
2004. Vol. 56, no 6, 849-857 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-72839DOI: 00006450-200412000-00003PubMedID: 15496608OAI: oai:DiVA.org:uu-72839DiVA: diva2:100750
Available from: 2005-05-30 Created: 2005-05-30 Last updated: 2009-10-13Bibliographically approved
In thesis
1. Teratogenicity Involved in Experimental Diabetic Pregnancy
Open this publication in new window or tab >>Teratogenicity Involved in Experimental Diabetic Pregnancy
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Maternal diabetes is associated with increased risk of growth disturbances and congenital malformations. The malformations rate in the offspring of diabetic mothers is 2-3 fold higher compared to infants of nondiabetic mothers. In this thesis we have investigated the role of the protein kinase C (PKC) pathway and the apoptotic machinery in embryopathy.

We investigated the involvement of PKC isoforms in the embryopathy of diabetic rat pregnancy. Embryos of diabetic rats showed altered activity and protein distribution of several PKC isoforms compared with embryos of normal rats. Using whole embryo culture we found increased activity of PKC-delta and PKC-zeta after 24h of culture and increased rate of malformations and growth retardation in embryos cultured in high glucose concentration compared to embryos cultured in low glucose concentration. Addition of α-cyano-4-cinnamic acid and N-acetylcysteine to the culture medium normalized malformations and growth retardations whereas specific PKC-inhibitors abolished malformations and partly restored the growth retardations. All treatment normalized glucose-induced increase of PKC activity.

Estimated occurrence of apoptosis in embryos of diabetic rats and in embryonic cells exposed to high glucose concentration showed increased rate of pro-apoptotic markers. The increased apoptosis in the high glucose exposed embryonic cells was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. Treatment with vitamin E and folic acid to diabetic pregnant rats decreased diabetes-induced malformations and resorptions, concomitant with normalization of apoptotic protein levels.

These results suggest that oxidative stress is augmented in embryos of diabetic rats and that it also plays a role in the activation of PKC and apoptosis. We used antioxidative treatment with beneficial effect although we could not completely abolish the embryonic demise; this may indicate that other mechanisms are involved in diabetic embryopathy. Further studies are needed to develop multi-nutrient dietary supplement to eliminate embryonic abnormalities induced by maternal diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 187
Keyword
Cell biology, Diabetes, Pregnancy, PKC, Apoptosis, Rat, Embryopathy, Vitamin E, Folic acid, CHC, NAC, Cellbiologi
Identifiers
urn:nbn:se:uu:diva-7203 (URN)91-554-6690-7 (ISBN)
Public defence
2006-11-25, B21, Biomedicinskt centrum, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2009-10-14Bibliographically approved

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Gäreskog, MattiasWentzel, Parri

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