Down-regulation of endothelin-1 receptors by protein kinase C in streptozotocin diabetic rats.
The vasoconstrictor response is defective in diabetes mellitus (DM). Activation of protein kinase C (PKC) is also known to prevail in diabetes mellitus, and it is thought to be secondary to abnormal diacylglycerol metabolism. To ascertain whether this PKC activation in diabetes underlies the vasomotor defect by regulating biological receptors, we studied the characteristics of the receptor for endothelin (ET), "the vasoconstrictor of injury." For this purpose, diabetes was induced in rats by intravenous streptozotocin. One to 2 weeks after streptozotocin treatment (average glucose at time of experiments: 518 mg/dl), glomeruli were isolated and assessed for ET receptor and PKC activity. ET receptor characteristics were also assessed following infusion of a specific PKC inhibitor, 1-(5-isoquinolinesulfonyl)piperazine (CI). For comparison, nondiabetic controls with and without PKC inhibitor were studied. No differences in high-affinity ET-1 receptor (ER-1) characteristics were found among the diabetic and normal rats. In contrast, receptor density for the lower-affinity receptor (ER-2) was significantly depressed in DM without changes in the equilibrium dissociation constant. Infusion of CI 20 min before glomerular harvesting did not affect the glomerular PKC activity in controls (particulate: 28.0 +/- 4.0% of total activity to 22.0 +/- 3.9%, n = 3). In contrast, in diabetes mellitus rats infused with CI, PKC activity decreased (particulate: from 44.7 +/- 2.9% of total activity to 18.5 +/- 3.2%, n = 3, p less than 0.05). This CI-induced suppression of PKC in DM was accompanied by complete reversal in down-regulation of ER-2 receptors. Thus, DM is characterized by down-regulation in low-affinity ET-1 receptors. Furthermore, this receptor down-regulation can be reversed by abolishing abnormally enhanced PKC activity. These results indicate that abnormal activation of PKC may underlie the profoundly vasodilative status and defective vasoconstrictor response characterizing DM.
Awazu
M
M
Department of Pediatrics and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Parker
R E
RE
Harvie
B R
BR
Ichikawa
I
I
Kon
V
V
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation; D016232:Endothelins / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000201:enzymology / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017466:Receptors, Endothelin
D001786:Blood Glucose; D016232:Endothelins; D007546:Isoquinolines; D010879:Piperazines; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D000804:Angiotensin II; C052422:1-(5-isoquinolinesulfonyl)piperazine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C