Prasad Konkalmatt - Academia.edu (original) (raw)

Papers by Prasad Konkalmatt

International Journal of Molecular Sciences

Renal luminal sodium transport is essential for physiological blood pressure control, and abnorma... more Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Recently, we showed that GPCR 37L1 (GPR37L1) is expressed on the apical membrane of renal proximal tubules (RPT) and regulates luminal sodium transport and blood pressure by modulating the function of the sodium proton exchanger 3 (NHE3). However, little is known about GPR37L1 intracellular signaling. Here, we show that GPR37L1 is localized to the nuclear membrane, in addition to the plasma membrane in human RPT cells. Furthermore, GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhance NHE3 transcription. Overall, we demonstrate the direct role of a nuclear ...

Hypertension, 2015

GPR37 and GPR37L1 are closely related G-protein coupled receptors that are expressed mainly in br... more GPR37 and GPR37L1 are closely related G-protein coupled receptors that are expressed mainly in brain glial cells and muscle-myenteric nerve layers in the GI tract. GPR37L1 transgenic mice have decreased systolic blood pressure (SBP) whereas GPR37L1 KO mice have increased SBP. However, there are no studies reporting kidney expression of GPR37 or GPR37L1 or their role in renal blood pressure regulation. Immunostaining and immunoblotting showed that GPR37 and GPR37L1 are expressed in the apical membrane of proximal tubules of the mouse kidney; RT-PCR on proximal tubule and collecting duct cells obtained by laser capture micro-dissection of mouse kidney sections, confirmed these findings. In addition, chronic high salt diet increased the renal expression of prosaposin, a precursor for saposin C, a natural ligand for GPR37 and GPR37L1. Infusion of prosaptide, a synthetic ligand for GPR37 and GPR37L1, decreased SBP in mice by 10 mm Hg. To determine the roles of GPR37 and GPR37L1 in renal ...

Supplemental data of "Stomach Gastrin is Regulated by Sodium via PPAR-a and Dopamine D<su... more Supplemental data of "Stomach Gastrin is Regulated by Sodium via PPAR-a and Dopamine D₁ Receptor"<b></b>

International Journal of Molecular Sciences, 2021

The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins... more The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins. SNXs are characterized by the presence of a common phox-homology (PX) domain, along with other functional domains that play versatile roles in cellular signaling and membrane trafficking. In addition to the PX domain, the SNX-PXA-RGS-PXC subfamily, except for SNX19, contains a unique RGS (regulators of G protein signaling) domain that serves as GTPase activating proteins (GAPs), which accelerates GTP hydrolysis on the G protein α subunit, resulting in termination of G protein-coupled receptor (GPCR) signaling. Moreover, the PX domain selectively interacts with phosphatidylinositol-3-phosphate and other phosphoinositides found in endosomal membranes, while also associating with various intracellular proteins. Although SNX19 lacks an RGS domain, all members of the SNX-PXA-RGS-PXC subfamily serve as dual regulators of receptor cargo signaling and endosomal trafficking. This review discuss...

Journal of the American Heart Association, 2020

Background The regulation of sodium excretion is important in the pathogenesis of hypertension an... more Background The regulation of sodium excretion is important in the pathogenesis of hypertension and salt sensitivity is predictive of cardiovascular events and mortality. C57Bl/6 and BALB /c mice have different blood pressure sensitivities to salt intake. High salt intake increases blood pressure in some C57Bl/6J mouse strains but not in any BALB /c mouse strain. Methods and Results We determined the cause of the difference in salt sensitivity between C57Bl/6 and BALB /c mice. Basal levels of superoxide and H 2 O 2 were higher in renal proximal tubule cells ( RPTC s) from BALB /c than C57Bl/6J mice. High salt diet increased H 2 O 2 production in kidneys from BALB /c but C57Bl/6J mice. High sodium concentration (170 mmol/L) in the incubation medium increased H 2 O 2 levels in BALB /c‐ RPTC s but not in C57Bl/6J‐ RPTC s. H 2 O 2 (10 μmol/L) treatment decreased sodium transport in RPTC s from BALB /c but not C57Bl/6J mice. Overexpression of catalase in the mouse kidney predisposed BALB ...

Journal of Neuroscience, 2015

An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens ... more An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine D1 versus D2 receptors, is implicated in the behavioral responses to psychostimulants. To provide further insight into the molecular mechanisms occurring in MSN subtypes by cocaine, we examined the transcription factor early growth response 3 (Egr3). We evaluated Egr3 because it is a target of critical cocaine-mediated signaling pathways and because Egr3-binding sites are found on promoters of key cocaine-associated molecules. We first used a RiboTag approach to obtain ribosome-associated transcriptomes from each MSN subtype and found that repeated cocaine administration induced Egr3 ribosome-associated mRNA in NAc D1-MSNs while reducing Egr3 in D2-MSNs. Using Cre-inducible adeno-associated viruses combined with D1-Cre and D2-Cre mouse lines, we observed that Egr3 overexpression in D1-MSNs enhances rewarding and locomotor responses to cocaine, whereas overexpression in D2-MSNs blunts these behaviors. miRNA knock-down of Egr3 in MSN subtypes produced opposite behavioral responses from those observed with overexpression. Finally, we found that repeated cocaine administration altered Egr3 binding to promoters of genes that are important for cocaine-mediated cellular and behavioral plasticity. Genes with increased Egr3 binding to promoters, Camk2␣, CREB, FosB, Nr4a2, and Sirt1, displayed increased mRNA in D1-MSNs and, in some cases, a reduction in D2-MSNs. Histone and the DNA methylation enzymes G9a and Dnmt3a displayed reduced Egr3 binding to their promoters and reduced mRNA in D1-MSNs. Our study provides novel insight into an opposing role of Egr3 in select NAc MSN subtypes in cocaine action.

Translational research : the journal of laboratory and clinical medicine, Jan 25, 2014

Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associat... more Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associated with increased cardiovascular risk and overall mortality. Salt sensitivity can be treated by reducing NaCl consumption. However, decreasing salt intake in some may actually increase cardiovascular risk, including an increase in blood pressure, that is, inverse salt sensitivity. Several genes have been associated with salt sensitivity and inverse salt sensitivity. Some of these genes encode proteins expressed in the kidney that are needed to excrete a sodium load, for example, dopamine receptors and their regulators, G protein-coupled receptor kinase 4 (GRK4). We review here research in this field that has provided several translational opportunities, ranging from diagnostic tests to gene therapy, such as (1) a test in renal proximal tubule cells isolated from the urine of humans that may determine the salt-sensitive phenotype by analyzing the recruitment of dopamine D1 receptors to th...

The FASEB Journal, 2014

Adeno-associated viral (AAV) vectors provide sustained long-term gene expression with minimal imm... more Adeno-associated viral (AAV) vectors provide sustained long-term gene expression with minimal immunological consequences. Therefore AAV vector systems are useful gene-transfer tools in translationa...

The FASEB Journal, 2015

The lack of dopamine D2 receptor (D2R) function in one or both kidneys in mice increases blood pr... more The lack of dopamine D2 receptor (D2R) function in one or both kidneys in mice increases blood pressure (BP) and vulnerability to renal inflammation. D2R downregulation in only one kidney by the un...

Circulation, Nov 10, 2015

<jats:p>In humans decreased dopamine D2 receptor (D2R) expression and function is associate... more <jats:p>In humans decreased dopamine D2 receptor (D2R) expression and function is associated hypertension and inflammation and fibrosis in renal proximal tubule cells. In mice selective D2R silencing in the kidney results in renal inflammation, injury and hypertension. We hypothesized that these alterations are ameliorated by rescue of renal D2R function. To test this hypothesis we silenced renal D2R expression by sub-capsular infusion of D2R siRNA (D2RsiRNA) using osmotic mini pumps (3 μg/day, n=6 per group). Mice treated with non-silencing siRNA (NS siRNA) served as controls. Two weeks after starting siRNA treatment, mice were treated with control AAV (CAAV) or AAV carrying wild-type D2R (D2RAAV) (n=3 per group, 1e+11 vgp/mouse). Two weeks following AAV treatment, blood pressure was measured and organs were collected. D2R expression was decreased in D2RsiRNA-treated kidneys compared with NSsiRNA-treated kidneys (54 ± 0.8 vs 100± 22 %; P&lt;0.05). D2RAAV treatment increased D2R expression (7.5-11-fold; P&lt;0.01) in both D2RsiRNA and NS siRNA-treated mice. Mice with silenced D2R expression (D2RsiRNA+CAAV) had increased systolic blood pressure (121±3 mmHg; P&lt;0.05) in comparison with the D2R rescued group ( D2RsiRNA+D2RAAV) (100±6 mm Hg), NSsiRNA+CAAV (101±4 mm Hg), or NS siRNA +D2RAAV (101±1 mm Hg). D2R silencing caused an increase in the expression of TNF-α, TGF-β1 and its downstream target fibronectin-1, as well as kidney injury molecule-1 and ki-67, a marker of cell proliferation. By contrast, the expression of these proteins was decreased or reversed to normal in the D2R-rescued group. Masson trichrome staining showed tubular atrophy, interstitial fibrosis and extensive areas of scaring in D2R silenced mice while these abnormalities were significantly reduced in the D2R rescued group. T cells infiltration was significantly higher in D2R silenced group compared to the D2R-rescued group (309 ± 38 vs 217± 17 %; P&lt;0.05). These results show that D2R re-expression prevented the progression of the lesions and demonstrate that increased blood pressure and renal injury due to D2R silencing could be rescued by over expression of D2R in the kidney using AAV9 vector. Furthermore, these data provide the basis for designing novel therapies for kidney disease.</jats:p>

Hypertension

We have reported that lack or downregulation of dopamine D(2) receptor (D 2 R) function in mice i... more We have reported that lack or downregulation of dopamine D(2) receptor (D 2 R) function in mice increases the vulnerability to renal inflammation independent of blood pressure and that the D 2 R negatively regulates inflammation and prevents injury in mouse renal proximal tubule cells (RPTCs). Some common single nucleotide polymorphisms (SNPs; rs 6276, 6277 and 1800497) in the human DRD2 gene are associated with decreased D 2 R expression and function, as well as high blood pressure. We tested the hypothesis that human RPTCs expressing these SNPs have increased expression of inflammatory markers and injury. We studied immortalized human RPTCs isolated from normal tissue of nephrectomies which were genotyped for the D 2 R SNPs; 10 cell lines were selected: wild type (WT) n=5; heterozygous for both rs6276 and 6277 n=3; heterozygous for both rs6276 and 1800497 n=2. All 5 cell lines expressing SNPs (hRPTC-SNP) had decreased D 2 R mRNA (0.52±0.03 vs. 1±0.02 (WT) fold; P<0.02 ) and pro...

Supplemental Material for the paper "Human Stomach Gastrin Secretion is Regulated by Sodium ... more Supplemental Material for the paper "Human Stomach Gastrin Secretion is Regulated by Sodium via PPAR-alpha Pathway and Modulated by the Dopamine 1 Receptor "

Hypertension

Some common single nucleotide polymorphisms (rs6276 and rs6277, SNPs) of the human DRD2 gene are ... more Some common single nucleotide polymorphisms (rs6276 and rs6277, SNPs) of the human DRD2 gene are associated with decreased D2R expression and function and increased blood pressure or hypertension. Human renal proximal tubule cells (hRPTCs) from subjects carrying these SNPs (hRPTCs-SNPs) express elevated levels of proinflammatory and profibrotic proteins, indicating that the D2R has protective effects in these cells and that decreased D2R function may contribute to the susceptibility to renal disease associated with essential hypertension. Micro RNA 4301 (miR4301) is an intronic miRNA that resides in the second intron of the primary human DRD2 transcript. A mouse homolog of miR4301 has not been identified to date. We hypothesized that miR4301 expression and function are decreased in hRPTCs-SNPs and that loss of miR4301 mediates, in part, the deleterious effects of decreased D2R function. We studied four cell lines carrying no SNPs (hRPTCs-WT) and four hRPTCs-SNPs lines. miR4301 expre...

Circulation, 2012

Objectives: Expression of inducible nitric oxide synthase (iNOS) is dramatically increased in the... more Objectives: Expression of inducible nitric oxide synthase (iNOS) is dramatically increased in the heart after myocardial infarction (MI). Previous reports on the role of iNOS in post-MI left ventri...

Hypertension, 2015

Previous work from our laboratory indicates that the dopamine D2 receptor (D2R) in the kidney has... more Previous work from our laboratory indicates that the dopamine D2 receptor (D2R) in the kidney has a direct role in regulating renal inflammation and injury and blood pressure. Some common single nucleotide polymorphisms (D2R SNPs; rs 6276, 6277, and 1800497) in the human DRD2 gene are associated with decreased D2R expression and function. Immortalized renal proximal tubule cells (RPTCs) from subjects carrying D2R SNPs (RPTC-D2R SNPs) express less D2Rs than RPTCs carrying no D2R SNPs (RPTC-D2R WT) (62±4 vs 100±6%; P<0.04) and a pro-inflammatory and pro-fibrotic phenotype with markers of epithelial mesenchymal transition. RPTC-D2R SNPs showed increased apoptosis compared with RPTC-D2R WT (11± 0.8 vs 2.3±0.4% TUNEL positive cells, P<0.01, n=5/group). We hypothesized that the D2R regulates renal cell survival through effects on Wnt signaling. We found that Wnt3 expression was increased in RPTC-D2R SNPs compared with RPTC-D2R WT (mRNA: 2.6±0.35 vs 1±0.11 fold; P<0.05; protein: 1...

International Journal of Molecular Sciences

Renal luminal sodium transport is essential for physiological blood pressure control, and abnorma... more Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Recently, we showed that GPCR 37L1 (GPR37L1) is expressed on the apical membrane of renal proximal tubules (RPT) and regulates luminal sodium transport and blood pressure by modulating the function of the sodium proton exchanger 3 (NHE3). However, little is known about GPR37L1 intracellular signaling. Here, we show that GPR37L1 is localized to the nuclear membrane, in addition to the plasma membrane in human RPT cells. Furthermore, GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhance NHE3 transcription. Overall, we demonstrate the direct role of a nuclear ...

Hypertension, 2015

GPR37 and GPR37L1 are closely related G-protein coupled receptors that are expressed mainly in br... more GPR37 and GPR37L1 are closely related G-protein coupled receptors that are expressed mainly in brain glial cells and muscle-myenteric nerve layers in the GI tract. GPR37L1 transgenic mice have decreased systolic blood pressure (SBP) whereas GPR37L1 KO mice have increased SBP. However, there are no studies reporting kidney expression of GPR37 or GPR37L1 or their role in renal blood pressure regulation. Immunostaining and immunoblotting showed that GPR37 and GPR37L1 are expressed in the apical membrane of proximal tubules of the mouse kidney; RT-PCR on proximal tubule and collecting duct cells obtained by laser capture micro-dissection of mouse kidney sections, confirmed these findings. In addition, chronic high salt diet increased the renal expression of prosaposin, a precursor for saposin C, a natural ligand for GPR37 and GPR37L1. Infusion of prosaptide, a synthetic ligand for GPR37 and GPR37L1, decreased SBP in mice by 10 mm Hg. To determine the roles of GPR37 and GPR37L1 in renal ...

Supplemental data of "Stomach Gastrin is Regulated by Sodium via PPAR-a and Dopamine D<su... more Supplemental data of "Stomach Gastrin is Regulated by Sodium via PPAR-a and Dopamine D₁ Receptor"<b></b>

International Journal of Molecular Sciences, 2021

The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins... more The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins. SNXs are characterized by the presence of a common phox-homology (PX) domain, along with other functional domains that play versatile roles in cellular signaling and membrane trafficking. In addition to the PX domain, the SNX-PXA-RGS-PXC subfamily, except for SNX19, contains a unique RGS (regulators of G protein signaling) domain that serves as GTPase activating proteins (GAPs), which accelerates GTP hydrolysis on the G protein α subunit, resulting in termination of G protein-coupled receptor (GPCR) signaling. Moreover, the PX domain selectively interacts with phosphatidylinositol-3-phosphate and other phosphoinositides found in endosomal membranes, while also associating with various intracellular proteins. Although SNX19 lacks an RGS domain, all members of the SNX-PXA-RGS-PXC subfamily serve as dual regulators of receptor cargo signaling and endosomal trafficking. This review discuss...

Journal of the American Heart Association, 2020

Background The regulation of sodium excretion is important in the pathogenesis of hypertension an... more Background The regulation of sodium excretion is important in the pathogenesis of hypertension and salt sensitivity is predictive of cardiovascular events and mortality. C57Bl/6 and BALB /c mice have different blood pressure sensitivities to salt intake. High salt intake increases blood pressure in some C57Bl/6J mouse strains but not in any BALB /c mouse strain. Methods and Results We determined the cause of the difference in salt sensitivity between C57Bl/6 and BALB /c mice. Basal levels of superoxide and H 2 O 2 were higher in renal proximal tubule cells ( RPTC s) from BALB /c than C57Bl/6J mice. High salt diet increased H 2 O 2 production in kidneys from BALB /c but C57Bl/6J mice. High sodium concentration (170 mmol/L) in the incubation medium increased H 2 O 2 levels in BALB /c‐ RPTC s but not in C57Bl/6J‐ RPTC s. H 2 O 2 (10 μmol/L) treatment decreased sodium transport in RPTC s from BALB /c but not C57Bl/6J mice. Overexpression of catalase in the mouse kidney predisposed BALB ...

Journal of Neuroscience, 2015

An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens ... more An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine D1 versus D2 receptors, is implicated in the behavioral responses to psychostimulants. To provide further insight into the molecular mechanisms occurring in MSN subtypes by cocaine, we examined the transcription factor early growth response 3 (Egr3). We evaluated Egr3 because it is a target of critical cocaine-mediated signaling pathways and because Egr3-binding sites are found on promoters of key cocaine-associated molecules. We first used a RiboTag approach to obtain ribosome-associated transcriptomes from each MSN subtype and found that repeated cocaine administration induced Egr3 ribosome-associated mRNA in NAc D1-MSNs while reducing Egr3 in D2-MSNs. Using Cre-inducible adeno-associated viruses combined with D1-Cre and D2-Cre mouse lines, we observed that Egr3 overexpression in D1-MSNs enhances rewarding and locomotor responses to cocaine, whereas overexpression in D2-MSNs blunts these behaviors. miRNA knock-down of Egr3 in MSN subtypes produced opposite behavioral responses from those observed with overexpression. Finally, we found that repeated cocaine administration altered Egr3 binding to promoters of genes that are important for cocaine-mediated cellular and behavioral plasticity. Genes with increased Egr3 binding to promoters, Camk2␣, CREB, FosB, Nr4a2, and Sirt1, displayed increased mRNA in D1-MSNs and, in some cases, a reduction in D2-MSNs. Histone and the DNA methylation enzymes G9a and Dnmt3a displayed reduced Egr3 binding to their promoters and reduced mRNA in D1-MSNs. Our study provides novel insight into an opposing role of Egr3 in select NAc MSN subtypes in cocaine action.

Translational research : the journal of laboratory and clinical medicine, Jan 25, 2014

Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associat... more Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associated with increased cardiovascular risk and overall mortality. Salt sensitivity can be treated by reducing NaCl consumption. However, decreasing salt intake in some may actually increase cardiovascular risk, including an increase in blood pressure, that is, inverse salt sensitivity. Several genes have been associated with salt sensitivity and inverse salt sensitivity. Some of these genes encode proteins expressed in the kidney that are needed to excrete a sodium load, for example, dopamine receptors and their regulators, G protein-coupled receptor kinase 4 (GRK4). We review here research in this field that has provided several translational opportunities, ranging from diagnostic tests to gene therapy, such as (1) a test in renal proximal tubule cells isolated from the urine of humans that may determine the salt-sensitive phenotype by analyzing the recruitment of dopamine D1 receptors to th...

The FASEB Journal, 2014

Adeno-associated viral (AAV) vectors provide sustained long-term gene expression with minimal imm... more Adeno-associated viral (AAV) vectors provide sustained long-term gene expression with minimal immunological consequences. Therefore AAV vector systems are useful gene-transfer tools in translationa...

The FASEB Journal, 2015

The lack of dopamine D2 receptor (D2R) function in one or both kidneys in mice increases blood pr... more The lack of dopamine D2 receptor (D2R) function in one or both kidneys in mice increases blood pressure (BP) and vulnerability to renal inflammation. D2R downregulation in only one kidney by the un...

Circulation, Nov 10, 2015

<jats:p>In humans decreased dopamine D2 receptor (D2R) expression and function is associate... more <jats:p>In humans decreased dopamine D2 receptor (D2R) expression and function is associated hypertension and inflammation and fibrosis in renal proximal tubule cells. In mice selective D2R silencing in the kidney results in renal inflammation, injury and hypertension. We hypothesized that these alterations are ameliorated by rescue of renal D2R function. To test this hypothesis we silenced renal D2R expression by sub-capsular infusion of D2R siRNA (D2RsiRNA) using osmotic mini pumps (3 μg/day, n=6 per group). Mice treated with non-silencing siRNA (NS siRNA) served as controls. Two weeks after starting siRNA treatment, mice were treated with control AAV (CAAV) or AAV carrying wild-type D2R (D2RAAV) (n=3 per group, 1e+11 vgp/mouse). Two weeks following AAV treatment, blood pressure was measured and organs were collected. D2R expression was decreased in D2RsiRNA-treated kidneys compared with NSsiRNA-treated kidneys (54 ± 0.8 vs 100± 22 %; P&lt;0.05). D2RAAV treatment increased D2R expression (7.5-11-fold; P&lt;0.01) in both D2RsiRNA and NS siRNA-treated mice. Mice with silenced D2R expression (D2RsiRNA+CAAV) had increased systolic blood pressure (121±3 mmHg; P&lt;0.05) in comparison with the D2R rescued group ( D2RsiRNA+D2RAAV) (100±6 mm Hg), NSsiRNA+CAAV (101±4 mm Hg), or NS siRNA +D2RAAV (101±1 mm Hg). D2R silencing caused an increase in the expression of TNF-α, TGF-β1 and its downstream target fibronectin-1, as well as kidney injury molecule-1 and ki-67, a marker of cell proliferation. By contrast, the expression of these proteins was decreased or reversed to normal in the D2R-rescued group. Masson trichrome staining showed tubular atrophy, interstitial fibrosis and extensive areas of scaring in D2R silenced mice while these abnormalities were significantly reduced in the D2R rescued group. T cells infiltration was significantly higher in D2R silenced group compared to the D2R-rescued group (309 ± 38 vs 217± 17 %; P&lt;0.05). These results show that D2R re-expression prevented the progression of the lesions and demonstrate that increased blood pressure and renal injury due to D2R silencing could be rescued by over expression of D2R in the kidney using AAV9 vector. Furthermore, these data provide the basis for designing novel therapies for kidney disease.</jats:p>

Hypertension

We have reported that lack or downregulation of dopamine D(2) receptor (D 2 R) function in mice i... more We have reported that lack or downregulation of dopamine D(2) receptor (D 2 R) function in mice increases the vulnerability to renal inflammation independent of blood pressure and that the D 2 R negatively regulates inflammation and prevents injury in mouse renal proximal tubule cells (RPTCs). Some common single nucleotide polymorphisms (SNPs; rs 6276, 6277 and 1800497) in the human DRD2 gene are associated with decreased D 2 R expression and function, as well as high blood pressure. We tested the hypothesis that human RPTCs expressing these SNPs have increased expression of inflammatory markers and injury. We studied immortalized human RPTCs isolated from normal tissue of nephrectomies which were genotyped for the D 2 R SNPs; 10 cell lines were selected: wild type (WT) n=5; heterozygous for both rs6276 and 6277 n=3; heterozygous for both rs6276 and 1800497 n=2. All 5 cell lines expressing SNPs (hRPTC-SNP) had decreased D 2 R mRNA (0.52±0.03 vs. 1±0.02 (WT) fold; P<0.02 ) and pro...

Supplemental Material for the paper "Human Stomach Gastrin Secretion is Regulated by Sodium ... more Supplemental Material for the paper "Human Stomach Gastrin Secretion is Regulated by Sodium via PPAR-alpha Pathway and Modulated by the Dopamine 1 Receptor "

Hypertension

Some common single nucleotide polymorphisms (rs6276 and rs6277, SNPs) of the human DRD2 gene are ... more Some common single nucleotide polymorphisms (rs6276 and rs6277, SNPs) of the human DRD2 gene are associated with decreased D2R expression and function and increased blood pressure or hypertension. Human renal proximal tubule cells (hRPTCs) from subjects carrying these SNPs (hRPTCs-SNPs) express elevated levels of proinflammatory and profibrotic proteins, indicating that the D2R has protective effects in these cells and that decreased D2R function may contribute to the susceptibility to renal disease associated with essential hypertension. Micro RNA 4301 (miR4301) is an intronic miRNA that resides in the second intron of the primary human DRD2 transcript. A mouse homolog of miR4301 has not been identified to date. We hypothesized that miR4301 expression and function are decreased in hRPTCs-SNPs and that loss of miR4301 mediates, in part, the deleterious effects of decreased D2R function. We studied four cell lines carrying no SNPs (hRPTCs-WT) and four hRPTCs-SNPs lines. miR4301 expre...

Circulation, 2012

Objectives: Expression of inducible nitric oxide synthase (iNOS) is dramatically increased in the... more Objectives: Expression of inducible nitric oxide synthase (iNOS) is dramatically increased in the heart after myocardial infarction (MI). Previous reports on the role of iNOS in post-MI left ventri...

Hypertension, 2015

Previous work from our laboratory indicates that the dopamine D2 receptor (D2R) in the kidney has... more Previous work from our laboratory indicates that the dopamine D2 receptor (D2R) in the kidney has a direct role in regulating renal inflammation and injury and blood pressure. Some common single nucleotide polymorphisms (D2R SNPs; rs 6276, 6277, and 1800497) in the human DRD2 gene are associated with decreased D2R expression and function. Immortalized renal proximal tubule cells (RPTCs) from subjects carrying D2R SNPs (RPTC-D2R SNPs) express less D2Rs than RPTCs carrying no D2R SNPs (RPTC-D2R WT) (62±4 vs 100±6%; P<0.04) and a pro-inflammatory and pro-fibrotic phenotype with markers of epithelial mesenchymal transition. RPTC-D2R SNPs showed increased apoptosis compared with RPTC-D2R WT (11± 0.8 vs 2.3±0.4% TUNEL positive cells, P<0.01, n=5/group). We hypothesized that the D2R regulates renal cell survival through effects on Wnt signaling. We found that Wnt3 expression was increased in RPTC-D2R SNPs compared with RPTC-D2R WT (mRNA: 2.6±0.35 vs 1±0.11 fold; P<0.05; protein: 1...