Inhibition of D ₄ Dopamine Receptors on Insulin Receptor Expression and Effect in Renal Proximal Tubule Cells

Abstract

BackgroundIon 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).Methods and ResultsInsulin 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.ConclusionsActivation 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.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

“…Regarding insulin, a short exposition to it (until 30 minutes) raised NKA activity [160,161,164], whereas exposition for more than 24 hours reduced NKA activity in rat PT cultures [165]. In the same way, in a culture complex model, insulin exposition raised renal NKA activity in the first 30 minutes, but it returned to the baseline levels after 2 hours and was even lower at 48-hour measurements [166].…”

“…Nevertheless, the results' heterogeneity does not allow to clearly define the insulin effect on NKA. In complex models of animal PT cultures, NKA activity increased after short exposition to insulin but decreased under sustained stimulus [160,161,[164][165][166][167]. In human tubular cell cultures, glucose inhibited while C-peptide stimulated NKA activity [143,168].…”

Role of GRK4 in the regulation of the renal ETB receptor in hypertension

“…Na + -K + -ATPase activity was the difference between ATP hydrolysis in the absence and presence of ouabain according, as we have previously described. 23 RPT cells were washed twice with 5 mL of ice-cold phosphate-free buffer and centrifuged at 3000 g for 10 minutes. Thereafter, the cells were lysed in 2 mL lysis buffer (5 mmol/L of MgCl 2 , 2 mmol/L of CaCl 2 , and 1 mmol/L of NaHCO 3 ) and centrifuged at 3000 g for 2 minutes.…”

Intranasal insulin treatment restores cognitive deficits and insulin signaling impairment induced by repeated methamphetamine exposure

“…Several line of evidence show that MA induces oxidative stress, mitochondrial dysfunction, and neuroinflammation which all can impair insulin signaling . In a recent study it is shown that activation of dopamine D4 receptors, in rat renal proximal tubule cells, reduces the gene expression of IR . Considering the effects of MA on brain dopamine levels and activation of dopamine receptors, implication of such mechanism in brain needs to be investigated.…”