Enhancement of glomerular platelet-derived growth factor beta-receptor tyrosine phosphorylation in hypertensive rats and its inhibition by calcium channel blocker.
The molecular mechanism of glomerular injury in hypertension remains to be clarified. In this study, to examine the possible role of platelet-derived growth factor (PDGF) receptors in hypertensive glomerular injury, we specifically measured glomerular PDGF receptor tyrosine phosphorylation in various models of hypertensive rats using immunoprecipitation and Western blot analysis. A high-salt diet significantly enhanced glomerular PDGF beta-receptor tyrosine phosphorylation of Dahl-salt sensitive rats (DS-rats) without an increase in its protein levels, and this enhancement was associated with an elevation of blood pressure and glomerular injury. Stroke-prone spontaneously hypertensive rats (SHRSP) at hypertensive phase also had higher glomerular PDGF beta-receptor tyrosine phosphorylation levels than control Wistar-Kyoto rats (WKY), while SHR did not. Thus, DS-rats and SHRSP, which are well known to represent severe glomerular injury, had the enhanced PDGF beta-receptor tyrosine phosphorylation, while SHR, a hypertensive model without significant glomerular injury had no increased tyrosine phosphorylation. Treatment of DS-rats or SHRSP with benidipine, a calcium channel blocker, significantly lessened the increase in glomerular PDGF beta-receptor tyrosine phosphorylation, reduction of urinary protein and albumin excretion. These results suggest that the enhanced activation of glomerular PDGF beta-receptors may be responsible for the development of hypertensive glomerular injury and that the suppression of this receptor activation by a calcium channel blocker may contribute to its renal protective effects.
Zhan
Yumei
Y
Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
Kim
Shokei
S
Kawano
Hitomi
H
Iwao
Hiroshi
H
D000419:Albuminuria; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011507:Proteinuria / Q000652:urine; D051381:Rats; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR / Q000235:genetics; D011921:Rats, Inbred WKY; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D020521:Stroke / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014443:Tyrosine; C061004:benidipine; D020797:Receptor, Platelet-Derived Growth Factor beta