Abstract: FR-PO401
D4 Dopamine Receptors Regulate Insulin and Salt Sensitivities in Mice
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Liu, Mingda, Nanjing BenQ Medical Center, Nanjing, Jiangsu, China
- Zhang, Mingzhuo, Nanjing BenQ Medical Center, Nanjing, Jiangsu, China
- Wang, Weiwan, Nanjing BenQ Medical Center, Nanjing, Jiangsu, China
- Wang, Ping, Nanjing BenQ Medical Center, Nanjing, Jiangsu, China
- Wang, Xiaoyan, Nanjing BenQ Medical Center, Nanjing, Jiangsu, China
Background
Insulin resistance associated with dysfunction of dopamine receptors is underlined by multiple metabolic disorders including diabetes and hypertension. Dopamine D4 receptor(D4R)null mice are hypertensive.
Methods
To explore the effects of D4R on insulin resistance and hypertension, we determined the insulin/salt sensitivities, renal insulin pathway and sodium transporters in D4R null mice.
Results
Drd4-/- mice(14mos)had increased fasting blood glucose regardless of sex. Serum insulin levels at fasting were increased in male but not in female Drd4-/- mice. The male and female Drd4-/- mice presented a blunted blood glucose lowering effect at 30, 45 min after insulin injection (0.75U/kg,I.P).Their body weights, fasting serum total and free cholesterols, triglycerides were similar between the mouse strains. D4R agonist(PD168077,1mg/kg)increased but D4R antagonist(L745870,1mg/kg)decreased insulin sensitivity of D4+/+ mice via osmotic mini-pumps for a week. Changing the salt intake from low to high increased mean arterial pressure by 25±4% in D4-/- but only by 13±1% in D4+/+ mice while switching from high salt to low salt decreased it by 20±1% in D4-/- and by 11±3% in D4+/+ mice (tail-cuff, BP-98A, Softron, Tokyo, Japan). The higher salt-sensitivity in KO than WT was also confirmed by telemetry measurements. Less increase in urinary sodium excretion was found in D4-/- than in D4+/+ on high salt diet with a right-shift of pressure-natriuresis in D4-/-. On normal salt diet Drd4-/- mice had decreased IRβ（19±4, % of controls, n=4）but normal protein expressions of IRα, insulin degrading enzyme, insulin substrate 1, sodium glucose transporter 2 and glucose transporters in renal cortex homogenates. D4R and IRβ were co-immunoprecipitated in immortalized mouse renal distal convoluted tubule cells and the co-immunoprecipitation was increased by D4R agonist and not altered by D4R antagonist. IRβ was co-located with the apical NKCC2 in the thick ascending limbs of the Henle’s loop and NCC in the distal convoluted tubules but not with NHE3 in proximal convoluted tubules. NHE3 (126 ± 8), NKCC2 (182 ± 26) and NCC (226 ± 30) were increased in whole kidney homogenates of D4-/- while ENaCs and αNKA were similar between strains.
Conclusion
Therefore, D4R interacts with renal IRβ, NKCC2 and NCC,and may normalize blood pressures via reducing insulin resistance.