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1 Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA
2 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: schu{at}hsc.unt.edu.
Kidney glomeruli are important targets of diabetic nephropathy. We hypothesized a high concentration of glucose could suppress glomerular eNOS by a protein kinase C mechanism, as has been found in other tissues. Mouse kidney slices (150-200 µm) were bathed in Hank's solution with 100 µM L-arginine and exposed to either 5 mM or 20-30 mM D-glucose. Immunofluorescence identified only eNOS in normal mouse glomeruli. Measurements of glomerular NO concentration with NO-sensitive fluorescent dye (DAF2-DA) using confocal microscopy and NO-sensitive microelectrodes verified that resting glomeruli had active production of NO that was inhibited by L-NAME. High concentration (20 mM - 30 mM) D-glucose inhibited 60%-70% of the NO production within 15-30 minutes; L-glucose at same concentration did not have any effect. Inhibition of PKC-
with 100nM ruboxistaurin prevented eNOS suppression in high glucose media. Activation of protein kinase C with 100nM phorbol ester also suppressed the glomerular NO concentration. We concluded that eNOS in the renal glomerular capillary endothelial cells is suppressed by activity of PKC at high glucose concentrations comparable to those in diabetic animals and humans. The consequence is a rapid decline in the generation of NO in the glomerular endothelial cells in the presence of a high concentration of glucose.
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