Fenoldopam Treatment Improves Peripheral Insulin Sensitivity and Renal Function in STZ‐Induced Type 2 Diabetic Rats

Umrani, Dhananjay N.; Goyal, Ramesh K.

doi:10.1081/ceh-120020392

Cited by 14 publications

(16 citation statements)

References 27 publications

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“…The renal dopaminergic system is impaired in hyperinsulinemic rats and type 2 diabetes patients [26-28]. The dopamine D 1 -like receptor agonist, fenoldopam, has been shown to improve peripheral insulin sensitivity in STZ-induced type 2 diabetic rats [29]. In pancreatic beta cells, the D 2 -like receptor (D 2 R/D 3 R) agonist quinpirole inhibits glucose-stimulated insulin secretion [30].…”

Section: Discussionmentioning

confidence: 99%

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Wang

Han

et al. 2014

Cardiovasc Diabetol

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Vascular smooth muscle cells (VSMCs) proliferation and migration, which are central in the development of vascular diseases, are regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates VSMCs proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMCs proliferation. We hypothesize that activation of the D4 dopamine receptor may also inhibit the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. Our current study found that insulin increased the proliferation and migration of A10 cells, an effect that was reduced in the presence of a D4 receptor agonist, PD168077. The negative effect of the D4 receptor on insulin’s action may be via decreasing insulin receptor expression, because activation of the D4 receptor inhibited insulin receptor protein and mRNA expressions, indicating that the regulation occured at the transcriptional or post-transcriptional levels. To determine whether or not the inhibition of D4 receptor on insulin-mediated proliferation and migration of VSMCs has physiological significance, hyper-insulinemic Sprague–Dawley rats with balloon-injured carotid artery were treated with a D4 agonist, PD168077, (6 mg/kg/d) for 14 days. We found that PD168077 significantly inhibited neointimal formation by inhibition of VSMC proliferation. This study suggests that activation of the D4 receptor suppresses the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. The D4 receptor may be a potential therapeutic target to reduce the effects of insulin on artery remodeling.

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Section: Discussionmentioning

confidence: 99%

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Wang

Han

et al. 2014

Cardiovasc Diabetol

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“…The D 1 R-like receptor agonist fenoldopam improves the decreased insulin sensitivity and impaired natriuresis in streptozotocin-induced type 2 diabetes in rats (36,37). By contrast, high insulin levels decrease D 1 R protein expression in the plasma membrane of RPTCs (38).…”

Section: Discussionmentioning

confidence: 84%

Sorting Nexin 5 and Dopamine D1 Receptor Regulate the Expression of the Insulin Receptor in Human Renal Proximal Tubule Cells

Yang

Jones

et al. 2015

Endocrinology

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Sorting nexin 5 (SNX5) belongs to the SNX family, which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins, receptors, and transporters. SNX5 is important in the resensitization of the dopamine D1-like receptor (D1R). D1R is uncoupled from its effector proteins in hypertension and diabetes, and treatment of diabetes restores D1R function and insulin receptor (IR) expression. We tested the hypothesis that the D1R and SNX5 regulate IR by studying the expression, distribution, dynamics, and functional consequences of their interaction in human renal proximal tubule cells (hRPTCs). D1R, SNX5, and IR were expressed and colocalized in the brush border of RPTs. Insulin promoted the colocalization of SNX5 and IR at the perinuclear area of hRPTCs. Unlike SNX5, the D1R colocalized and coimmunoprecipitated with IR, and this interaction was enhanced by insulin. To evaluate the role of SNX5 and D1R on IR signaling, we silenced via RNA interference the endogenous expression of SNX5 or the D1R gene DRD1 in hRPTCs. We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B, which are crucial components of the IR signal transduction pathway. Our data indicate that SNX5 and D1R are necessary for normal IR expression and activity. It is conceivable that D1R and SNX5 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling.

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“…Activation of D 2 receptor with bromocriptine simultaneously ameliorates insulin levels in obese humans 11. Fenoldopam treatment improves peripheral insulin sensitivity and renal effect in STZ‐induced type 2 diabetic rats 12. Therefore, we hypothesize that D 4 receptor, along with insulin receptor in RPTs, might affect insulin receptor expression and effect.…”

Section: Discussionmentioning

confidence: 97%

“…Increasing pieces of evidence show interactions between insulin and dopamine receptors 10, 11, 12, 13. Hyperinsulinemic animals and patients have a defective renal dopaminergic system10; activation of dopamine receptor ameliorates insulin levels in obese humans and improves peripheral insulin sensitivity and renal function in streptozotocin (STZ)‐induced type 2 diabetic rats 11, 12.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Ren

et al. 2016

JAHA

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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.

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Fenoldopam Treatment Improves Peripheral Insulin Sensitivity and Renal Function in STZ‐Induced Type 2 Diabetic Rats

Cited by 14 publications

References 27 publications

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Sorting Nexin 5 and Dopamine D1 Receptor Regulate the Expression of the Insulin Receptor in Human Renal Proximal Tubule Cells

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

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Fenoldopam Treatment Improves Peripheral Insulin Sensitivity and Renal Function in STZ‐Induced Type 2 Diabetic Rats

Cited by 14 publications

References 27 publications

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Dopamine D4 receptors inhibit proliferation and migration of vascular smooth muscle cells induced by insulin via down-regulation of insulin receptor expression

Sorting Nexin 5 and Dopamine D1 Receptor Regulate the Expression of the Insulin Receptor in Human Renal Proximal Tubule Cells

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

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