GRK4-mediated adiponectin receptor-1 phosphorylative desensitization as a novel mechanism of reduced renal sodium excretion in hypertension

Abstract

Hypertensive patients have impaired sodium excretion. However, the mechanisms are incompletely understood. Despite the established association between obesity/excess adiposity and hypertension, whether and how adiponectin, one of the adipokines, contributes to impaired sodium excretion in hypertension has not been previously investigated. The current study tested the hypothesis that adiponectin promotes natriuresis and diuresis in the normotensive state. However, impaired adiponectin-mediated natriuresis and diuresis are involved in pathogenesis of hypertension. We found that sodium excretion was reduced in adiponectin knockout (Adipo−/−) mice; intrarenal arterial infusion of adiponectin-induced natriuresis and diuresis in Wistar–Kyoto (WKY) rats. However, the natriuretic and diuretic effects of adiponectin were impaired in spontaneously hypertensive rats (SHRs), which were ascribed to the hyperphosphorylation of adiponectin receptor and subsequent uncoupling from Gαi. Inhibition of adiponectin receptor phosphorylation by a specific point mutation restored its coupling with Gαi and the adiponectin-mediated inhibition of Na+-K+-ATPase activity in renal proximal tubule (RPT) cells from SHRs. Finally, we identified G protein-coupled receptor kinase 4 (GRK4) as a mediator of adiponectin receptor hyperphosphorylation; mice transgenic for a hyperphosphorylating variant of GRK4 replicated the abnormal adiponectin function observed in SHRs, whereas down-regulation of GRK4 by renal ultrasound-directed small interfering RNA (siRNA) restored the adiponectin-mediated sodium excretion and reduced the blood pressure in SHRs. We conclude that the stimulatory effect of adiponectin on sodium excretion is impaired in hypertension, which is ascribed to the increased renal GRK4 expression and activity. Targeting GRK4 restores impaired adiponectin-mediated sodium excretion in hypertension, thus representing a novel strategy against hypertension.

Synergistic Effect of Uroguanylin and D 1 Dopamine Receptors on Sodium Excretion in Hypertension

“… 42 Several studies have shown that the natriuretic effect of dopamine is mainly exerted via the D 1 ‐like receptors † . The impaired diuretic and natriuretic effects of D 1 ‐like receptors in SHRs 15 , 16 , 17 , 21 , 29 , 44 , 45 are due, in part, to hyperphosphorylation and desensitization of the renal D 1 R because of increased constitutive activity of the G protein‐coupled receptor kinase types 2 and 4. 15 , 16 , 17 , 21 , 29 , 46 , 47 , 48 , 49 Our present study found a synergistic effect between D 1 R and uroguanylin.…”

“…The impaired diuretic and natriuretic effects of D 1 ‐like receptors in SHRs 15 , 16 , 17 , 21 , 29 , 44 , 45 are due, in part, to hyperphosphorylation and desensitization of the renal D 1 R because of increased constitutive activity of the G protein‐coupled receptor kinase types 2 and 4. 15 , 16 , 17 , 21 , 29 , 46 , 47 , 48 , 49 Our present study found a synergistic effect between D 1 R and uroguanylin. Although subthreshold dosages of uroguanylin or fenoldopam had no effect, coinfusion of subthreshold dosages of those reagents significantly increased water and sodium excretion.…”

Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules

“…Alsters et al [ 67 ], Lee et al [ 68 ], Shiffman et al [ 69 ], Yaghootkar et al [ 70 ], Rotroff et al [ 71 ], Cheng et al [ 72 ], Baig et al [ 73 ], Zhang et al [ 74 ], Lebailly et al [ 75 ], Ferris et al [ 76 ], Lempainen et al [ 77 ] and McCallum et al [ 78 ] presented that high expression of CPE (carboxypeptidase E), RPL13A, CERS2, CCND2, PRPF31, SARM1, PLD1, EPHA4, ARNTL2, BATF3, IKZF4 and MEN1 were associated with diabetes, but these genes might be linked with advancement of PCOS. Wang et al [ 79 ], Tian et al [ 80 ], Zhang et al [ 81 ] and Carr et al [ 82 ] demonstrated that over expression of ATP6AP2, FIS1, GRK4 and KCNQ4 were found to be substantially related to hypertension, but these genes might be essential for PCOS progression. Atiomo et al [ 83 ], Lara et al [ 84 ] and Douma et al [ 85 ] were reported that NQO1, NGFR (nerve growth factor receptor) and ESR1 could be an index for PCOS.…”

QR code model: a new possibility for GPCR phosphorylation recognition

“…The downregulation of GRK2 expression overactivated the β 2 -AR/cAMP/PKA pathway in hepatocellular carcinoma, thereby promoting the growth of cancer cells [ 63 ]. GRK4-induced hyperphosphorylation of adiponectin receptors can lead to the development of hypertension [ 64 ]. These studies suggest that timely and appropriate phosphorylation ensures the accurate transmission of extracellular information by GPCRs and maintains homeostasis.…”