Inhibition of D4 Dopamine Receptors on Insulin Receptor Expression and Effect in Renal Proximal Tubule Cells.
Ion transport in the renal proximal tubule (RPT), which is increased in essential hypertension, is regulated by numerous hormones and humoral factors, including insulin and dopamine. Activation of dopamine receptor inhibits sodium reabsorption, whereas activation of insulin receptor increases sodium reabsorption in RPTs, and hyperinsulinemic animals and patients have defective renal dopaminergic system. We presume that there is an inhibition of D4 receptor on insulin receptor expression and effect, and the regulation is lost in spontaneously hypertensive rats (SHRs).



Insulin receptor expression was determined by immunoblotting, and Na(+)-K(+)-ATPase activity was detected in both Wistar-Kyoto (WKY) and SHR RPT cells. Stimulation of D4 receptor with PD168077 decreased expression of insulin receptors, which was blocked in the presence of the calcium-channel blocker, nicardipine (10(-6) mol/L per 24 hours), in cell culture medium without calcium or in the presence of inositol 1,4,5-trisphosphate (IP3) receptor blocker (2-aminoethyl diphenylborinate [2-ADB]; 10(-6) mol/L per 24 hours), indicating that extracellular calcium entry and calcium release from the endoplasmic reticulum were involved in the signal pathway. Stimulation of the insulin receptor stimulated Na(+)-K(+)-ATPase activity, whereas pretreatment with PD168077 for 24 hours decreased the inhibitory effects of insulin receptor on Na(+)-K(+)-ATPase activity in WKY cells. However, in SHR cells, inhibition of D4 receptor on insulin receptor expression and effect were lost.



Activation of D4 receptor inhibits insulin receptor expression in RPT cells from WKY rats. The aberrant inhibition of D4 receptor on insulin receptor expression and effect might be involved in the pathogenesis of essential hypertension.
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China.
Ye
Y
Zhang
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China.
Hongmei
H
Ren
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China.
Xi
X
Lu
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China.
Duofen
D
He
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China.
Yu
Y
Han
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China.
Hongyong
H
Wang
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China chunyuzeng01@163.com stonewb@163.com.
Chunyu
C
Zeng
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China Chongqing Institute of Cardiology, Chongqing, China chunyuzeng01@163.com stonewb@163.com.
Weibin
W
Shi
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000075222:Essential Hypertension; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D007424:Intracellular Fluid / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D012313:RNA / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000235:genetics*; D050638:Receptors, Dopamine D4 / Q000187:drug effects* / Q000378:metabolism
D001549:Benzamides; D002121:Calcium Channel Blockers; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010879:Piperazines; D050638:Receptors, Dopamine D4; D012313:RNA; D011972:Receptor, Insulin; D002118:Calcium
dopamine receptor; hypertension; insulin; renal proximal tubule cells