Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors

2001 ◽  
Vol 280 (2) ◽  
pp. F254-F265 ◽  
Author(s):  
George J. Wehbi ◽  
Joseph Zimpelmann ◽  
Robert M. Carey ◽  
David Z. Levine ◽  
Kevin D. Burns
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Expression ◽  
Mrna Expression ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Early Diabetes

The interaction of ANG II with intrarenal AT1 receptors has been implicated in the progression of diabetic nephropathy, but the role of intrarenal AT2 receptors is unknown. The present studies determined the effect of early diabetes on components of the glomerular renin-angiotensin system and on expression of kidney AT2receptors. Three groups of rats were studied after 2 wk: 1) control (C), 2) streptozotocin (STZ)-induced diabetic (D), and 3) STZ-induced diabetic with insulin implant (D+I), to maintain normoglycemia. By competitive RT-PCR, early diabetes had no significant effect on glomerular mRNA expression for renin, angiotensinogen, or angiotensin-converting enzyme (ACE). In isolated glomeruli, nonglycosylated (41-kDa) AT1 receptor protein expression (AT1A and AT1B) was increased in D rats, with no change in glycosylated (53-kDa) AT1 receptor protein or in AT1 receptor mRNA. By contrast, STZ diabetes caused a significant decrease in glomerular AT2 receptor protein expression (47.0 ± 6.5% of C; P < 0.001; n = 6), with partial reversal in D+I rats. In normal rat kidney, AT2 receptor immunostaining was localized to glomerular endothelial cells and tubular epithelial cells in the cortex, interstitial, and tubular cells in the outer medulla, and inner medullary collecting duct cells. STZ diabetes caused a significant decrease in AT2 receptor immunostaining in all kidney regions, an effect partially reversed in D+I rats. In summary, early diabetes has no effect on glomerular mRNA expression for renin, angiotensinogen, or ACE. AT2 receptors are present in glomeruli and are downregulated in early diabetes, as are all kidney AT2 receptors. Our data suggest that alterations in the balance of kidney AT1 and AT2 receptor expression may contribute to ANG II-mediated glomerular injury in progressive diabetic nephropathy.

scholarly journals Collecting duct (pro)renin receptor targets ENaC to mediate angiotensin II-induced hypertension

2017 ◽  
Vol 312 (2) ◽  
pp. F245-F253 ◽  
Author(s):  
Kexin Peng ◽  
Xiaohan Lu ◽  
Fei Wang ◽  
Adam Nau ◽  
Ren Chen ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Mrna Expression ◽  
Collecting Duct ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Mrna And Protein Expression ◽  
Receptor Targets

The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-epithelial sodium channel (α-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt-ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC.

scholarly journals RenalAT1Receptor Protein Expression During the Early Stage of Diabetes Mellitus

2002 ◽  
Vol 3 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Lisa M. Harrison-Bernard ◽  
John D. Imig ◽  
Pamela K. Carmines
Keyword(s):  
Diabetes Mellitus ◽  
Protein Expression ◽  
Early Stage ◽  
Collecting Duct ◽  
Receptor Protein ◽  
Cortical Collecting Duct ◽  
Distal Nephron ◽  
Protein Levels ◽  
Nephron Segments

Experiments were performed to evaluate the hypothesis that the early stage of Type 1 diabetes mellitus (DM) increases renal angiotensin II (AngII) concentration and angiotensin type 1 (AT1) receptor protein levels. Nineteen or twenty days after vehicle (Sham rats) or streptozotocin (STZ rats) treatment, plasma [AngII] was higher in STZ rats (152±23 fmol/ml) than in Sham rats (101±7 fmol/ml); however, kidney [AngII] did not differ between groups.AT1receptor protein expression was greater in STZ kidneys than in Sham kidneys. This increase was restricted to the cortex, whereAT1protein levels were elevated by 77±26% (42 kDa) and 101±16% (58 kDa) in STZ kidneys. Immunohistochemistry revealed this effect to be most evident in distal nephron segments including the connecting tubule/cortical collecting duct. Increased renal corticalAT1receptor protein and circulating AngII levels are consistent with an exaggerated AngII-dependent influence on renal function during the early stage of DM in the rat.

Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney

1998 ◽  
Vol 274 (3) ◽  
pp. F611-F622 ◽  
Author(s):  
Daniela Riccardi ◽  
Amy E. Hall ◽  
Naibedya Chattopadhyay ◽  
Jason Z. Xu ◽  
Edward M. Brown ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Regional Distribution ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Thick Ascending Limb ◽  
Polyvalent Cation ◽  
Amino Acid Region ◽  
Oxide Synthase ◽  
Brain Nitric Oxide ◽  
Cation Sensing

We previously identified transcripts encoding a G protein-coupled, extracellular calcium/polyvalent cation-sensing receptor, RaKCaR, in rat kidney (D. Riccardi, J. Park, W.-S. Lee, G. Gamba, E. M. Brown, and S. C. Hebert. Proc. Natl. Acad. Sci. USA 92: 131–135, 1994), which was proposed to provide the mechanism for modulating a variety of renal functions in response to changes in extracellular Ca2+ (E. M. Brown. In: Handbook of Physiology. Bethesda, MD: Am. Physiol. Soc., 1992, sect. 8, vol. 2, chapt. 39, p. 1841–1916; and S. C. Hebert. Kidney Int. 50: 2129–2139, 1996). Here, we examine the cellular and regional distribution of receptor protein by immunofluorescence microscopy using a polyclonal antibody raised against a 22 amino acid region of the NH2 terminus of the receptor. The most intense fluorescence was seen at the basolateral border of cortical thick ascending limb cells. Basolateral staining for the receptor was also detected in medullary thick ascending limbs, in macula densa cells identified by costaining with antibody to brain nitric oxide synthase, NOS-B1, and in distal convoluted tubule cells distinguished by costaining for the apical thiazide-sensitive Na+-Cl−cotransporter. Apical anti-RaKCaR staining was detected at the base of the brush border of proximal tubules with decreasing intensity from S1 to S3 segments. In cortical collecting ducts, anti-RaKCaR staining was detected in some, but not all, type A intercalated cells identified by costaining with anti-H+-ATPase and anti-AE1 Cl−/[Formula: see text]exchanger antibodies. The present study demonstrates that RaKCaR protein is expressed in many different nephron segments and that the polarity of receptor expression varies with cell type along the nephron. These results suggest potential roles for the extracellular Ca2+/polyvalent cation-sensing receptor in responding to both circulating and urinary concentrations of divalent minerals and potentially other polyvalent cations (e.g., aminoglycoside antibiotics) to modulate nephron function.

scholarly journals Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney

2012 ◽  
Vol 302 (5) ◽  
pp. F540-F551 ◽  
Author(s):  
Emily Borsting ◽  
Vicki Pei-Chun Cheng ◽  
Chris K. Glass ◽  
Volker Vallon ◽  
Robyn Cunard
Keyword(s):  
Protein Expression ◽  
Sodium Channel ◽  
Mrna Expression ◽  
Collecting Duct ◽  
Epithelial Sodium Channel ◽  
Duct Cell ◽  
Kidney Cortex ◽  
Peroxisome Proliferator ◽  
Cortical Collecting Duct ◽  
Peroxisome Proliferator Activated Receptor

Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, ∼5% of patients experience the treatment-limiting side effect of edema. Studies have implicated activation of the epithelial sodium channel (ENaC) as a cause of TZD-induced fluid retention, although there have been conflicting reports. The goal of this study was to resolve the role of PPARγ in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPARγ ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaCα and ENaCβ mRNA and ENaCγ protein expression in the kidney cortex, and acute treatment for 5 h with pioglitazone, another potent TZD, does not increase renal ENaC isoform mRNA or protein expression. Pioglitazone also decreases ENaCα and ENaCγ mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPARγ-dependent regulation of ENaC. Pioglitazone represses ENaCγ promoter activity, and this repression is partially relieved by inhibition of protein synthesis. Chromatin immunoprecipitation assays revealed that repression is associated with a decrease in histone H4K5 acetylation at the proximal ENaCγ promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaCγ promoter via an indirect transcriptional mechanism.

Renal expression of the ammonia transporters, Rhbg and Rhcg, in response to chronic metabolic acidosis

2006 ◽  
Vol 290 (2) ◽  
pp. F397-F408 ◽  
Author(s):  
Ramanathan M. Seshadri ◽  
Janet D. Klein ◽  
Shelley Kozlowski ◽  
Jeff M. Sands ◽  
Young-Hee Kim ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Protein Expression ◽  
Mrna Expression ◽  
Collecting Duct ◽  
Broad Band ◽  
Ammonia Excretion ◽  
Intercalated Cells ◽  
Outer Medulla ◽  
Chronic Metabolic Acidosis ◽  
Medullary Collecting Duct

Chronic metabolic acidosis induces dramatic increases in net acid excretion that are predominantly due to increases in urinary ammonia excretion. The current study examines whether this increase is associated with changes in the expression of the renal ammonia transporter family members, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg). Chronic metabolic acidosis was induced in Sprague-Dawley rats by HCl ingestion for 1 wk; control animals were pair-fed. After 1 wk, metabolic acidosis had developed, and urinary ammonia excretion increased significantly. Rhcg protein expression was increased in both the outer medulla and the base of the inner medulla. Intercalated cells in the outer medullary collecting duct (OMCD) and in the inner medullary collecting duct (IMCD) in acid-loaded animals protruded into the tubule lumen and had a sharp, discrete band of apical Rhcg immunoreactivity, compared with a flatter cell profile and a broad band of apical immunolabel in control kidneys. In addition, basolateral Rhcg immunoreactivity was observed in both control and acidotic kidneys. Cortical Rhcg protein expression and immunoreactivity were not detectably altered. Rhcg mRNA expression was not significantly altered in the cortex, outer medulla, or inner medulla by chronic metabolic acidosis. Rhbg protein and mRNA expression were unchanged in the cortex, outer and inner medulla, and no changes in Rhbg immunolabel were evident in these regions. We conclude that chronic metabolic acidosis increases Rhcg protein expression in intercalated cells in the OMCD and in the IMCD, where it is likely to mediate an important role in the increased urinary ammonia excretion.

scholarly journals Angiotensin II stimulates epithelial sodium channels in the cortical collecting duct of the rat kidney

2012 ◽  
Vol 302 (6) ◽  
pp. F679-F687 ◽  
Author(s):  
Peng Sun ◽  
Peng Yue ◽  
Wen-Hui Wang
Keyword(s):  
Angiotensin Ii ◽  
Single Channel ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Ang Ii ◽  
Cortical Collecting Duct ◽  
Patch Clamp Recording ◽  
Open Probability ◽  
Whole Cell ◽  
Na Currents

We examined the effect of angiotensin II (ANG II) on epithelial Na+channel (ENaC) in the rat cortical collecting duct (CCD) with single-channel and the perforated whole cell patch-clamp recording. Application of 50 nM ANG II increased ENaC activity, defined by NPo(a product of channel numbers and open probability), and the amiloride-sensitive whole cell Na currents by twofold. The stimulatory effect of ANG II on ENaC was absent in the presence of losartan, suggesting that the effect of ANG II on ENaC was mediated by ANG II type 1 receptor. Moreover, depletion of intracellular Ca2+with 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid (BAPTA)-AM failed to abolish the stimulatory effect of ANG II on ENaC but inhibiting protein kinase C (PKC) abolished the effect of ANG II, suggesting that the effect of ANG II was the result of stimulating Ca2+-independent PKC. This notion was also suggested by the experiments in which stimulation of PKC with phorbol ester derivative mimicked the effect of ANG II and increased amiloride-sensitive Na currents in the principal cell, an effect that was not abolished by treatment of the CCD with BAPTA-AM. Also, inhibition of NADPH oxidase (NOX) with diphenyleneiodonium chloride abolished the stimulatory effect of ANG II on ENaC and application of superoxide donors, pyrogallol or xanthine and xanthine oxidase, significantly increased ENaC activity. Moreover, addition of ANG II or H2O2diminished the arachidonic acid (AA)-induced inhibition of ENaC in the CCD. We conclude that ANG II stimulates ENaC in the CCD through a Ca2+-independent PKC pathway that activates NOX thereby increasing superoxide generation. The stimulatory effect of ANG II on ENaC may be partially the result of blocking AA-induced inhibition of ENaC.

scholarly journals COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla

2014 ◽  
Vol 307 (1) ◽  
pp. F25-F32 ◽  
Author(s):  
Fei Wang ◽  
Xiaohan Lu ◽  
Kexin Peng ◽  
Li Zhou ◽  
Chunling Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Renal Medulla ◽  
Receptor Expression ◽  
Ang Ii ◽  
Cox 2 ◽  
Renin Content

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

scholarly journals α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions

2021 ◽  
Vol 8 ◽  
Author(s):  
Aarón Guerrero ◽  
Bruna Visniauskas ◽  
Pilar Cárdenas ◽  
Stefanny M. Figueroa ◽  
Jorge Vivanco ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Angiotensin Ii ◽  
High Glucose ◽  
In Silico ◽  
Apical Membrane ◽  
Collecting Duct ◽  
Receptor Expression ◽  
Ang Ii ◽  
Diabetic Mice ◽  
Intracellular Ca

Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na+ reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na+ retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca2+ depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na+ reabsorption.

scholarly journals Sex-dependent expression of water channel AQP1 along the rat nephron

2015 ◽  
Vol 308 (8) ◽  
pp. F809-F821 ◽  
Author(s):  
Carol M. Herak-Kramberger ◽  
Davorka Breljak ◽  
Marija Ljubojević ◽  
Mirela Matokanović ◽  
Mila Lovrić ◽  
...  
Keyword(s):  
Protein Expression ◽  
Proximal Tubule ◽  
Mrna Expression ◽  
Plasma Membranes ◽  
Rat Kidney ◽  
Water Channel ◽  
Estradiol Treatment ◽  
Adult Rats ◽  
Aqp1 Expression

In the mammalian kidney, nonglycosylated and glycosylated forms of aquaporin protein 1 (AQP1) coexist in the luminal and basolateral plasma membranes of proximal tubule and descending thin limb. Factors that influence AQP1 expression in (patho)physiological conditions are poorly known. Thus far, only angiotensin II and hypertonicity were found to upregulate AQP1 expression in rat proximal tubule in vivo and in vitro (Bouley R, Palomino Z, Tang SS, Nunes P, Kobori H, Lu HA, Shum WW, Sabolic I, Brown D, Ingelfinger JR, Jung FF. Am J Physiol Renal Physiol 297: F1575–F1586, 2009), a phenomenon that may be relevant for higher blood pressure observed in men and male experimental animals. Here we investigated the sex-dependent AQP1 protein and mRNA expression in the rat kidney by immunochemical methods and qRT-PCR in tissue samples from prepubertal and intact gonadectomized animals and sex hormone-treated gonadectomized adult male and female animals. In adult rats, the overall renal AQP1 protein and mRNA expression was ∼80% and ∼40% higher, respectively, in males than in females, downregulated by gonadectomy in both sexes and upregulated strongly by testosterone and moderately by progesterone treatment; estradiol treatment had no effect. In prepubertal rats, the AQP1 protein expression was low compared with adults and slightly higher in females, whereas the AQP1 mRNA expression was low and similar in both sexes. The observed differences in AQP1 protein expression in various experiments mainly reflect changes in the glycosylated form. The male-dominant expression of renal AQP1 in rats, which develops after puberty largely in the glycosylated form of the protein, may contribute to enhanced fluid reabsorption following the androgen- or progesterone-stimulated activities of sodium-reabsorptive mechanisms in proximal tubules.

scholarly journals Electroacupuncture improves synaptic plasticity by regulating the 5-HT1A receptor in hippocampus of rats with chronic unpredictable mild stress

2020 ◽  
Vol 48 (5) ◽  
pp. 030006052091841
Author(s):  
Lixing Chen ◽  
Zengyu Yao ◽  
Shanshan Qu ◽  
Jialing Zhang ◽  
Jiping Zhang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mrna Expression ◽  
Hippocampal Neurons ◽  
Quantitative Polymerase Chain Reaction ◽  
Receptor Expression ◽  
Receptor Protein ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Expression Levels ◽  
Mrna Expression Levels

Objectives To investigate the antidepressant effects of electroacupuncture (EA) on chronic unpredictable mild stress (CUMS) in rats, as well as the effects of EA on hippocampal neurons, synaptic morphology, and 5-hydroxytryptamine (HT) receptor expression. Methods Forty adult male Wistar rats were randomly divided into normal control, CUMS, EA, and paroxetine groups. CUMS modeling was performed for 21 days, followed by 14 days of intervention: rats in the EA group underwent stimulation of GV20 and GV29 acupuncture points for 30 minutes daily; rats in the paroxetine group were administered paroxetine daily. Behavioral tests, transmission electron microscopy, western blotting, and real-time quantitative polymerase chain reaction were used to evaluate the effects of the intervention. Results EA treatment reversed the behavioral changes observed in rats due to CUMS modeling; it also improved the pathological changes in organelles and synaptic structures of hippocampal neurons, and upregulated the protein and mRNA expression levels of 5-HT1A receptor. There were no significant differences in 5-HT1B receptor protein and mRNA expression levels among the groups. Conclusions EA treatment can alleviate depression-like symptoms in CUMS rats. The underlying mechanism may include promoting the expression of 5-HT1A receptor mRNA and protein, thereby improving synaptic plasticity in the hippocampus.

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