Dense-core vesicle proteins IA-2 and IA-2β affect renin synthesis and secretion through the β-adrenergic pathway

IA-2 and IA-2β, major autoantigens in type 1 diabetes, are transmembrane proteins in dense-core vesicles, and their expression influences the secretion of hormones and neurotransmitters. The present experiments were performed to examine whether IA-2 and IA-2β modulate the release of renin from dense-core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I·ml−1·h−1) was significantly reduced in mice with null mutations in IA-2, IA-2β, or both IA-2 and IA-2β compared with wild-type mice (876 ± 113, 962 ± 130, and 596 ± 82 vs. 1,367 ± 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 ± 5.1, 39 ± 5.4, and 35.3 ± 5.5% of wild-type in IA-2−/−, IA-2β−/−, and IA-2/IA-2β−/− mice. Plasma aldosterone levels were not significantly different among genotypes. The regulation of PRC by furosemide and salt intake, and of aldosterone by salt intake, was maintained in all genotypes. IA-2 and IA-2β expression did not colocalize with renin but showed overlapping immunoreactivity with tyrosine hydroxylase. While propranolol reduced PRC in wild-type mice, it had no effect on PRC in IA-2/ IA-2β−/− mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2β−/− mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2β are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals.

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COX-2 activity determines the level of renin expression but is dispensable for acute upregulation of renin expression in rat kidneys

AJP Renal Physiology ◽

10.1152/ajprenal.00513.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. F1782-F1790 ◽

Cited By ~ 35

Author(s):

Corina Matzdorf ◽

A. Kurtz ◽

Klaus Höcherl

Keyword(s):

Salt Intake ◽

Plasma Renin ◽

Renin Activity ◽

Prolonged Treatment ◽

Left Renal Artery ◽

Mrna Levels ◽

Absolute Increase ◽

Renin Mrna ◽

Cox 2 ◽

Rat Kidneys

The role of cyclooxygenase 2 (COX-2) in the control of renin is still a matter of debate, since studies with COX-2-deficient mice or with COX-2 inhibitors produced conflicting findings. Therefore, we studied the effect of the COX-2 inhibitor SC-58236 on the regulation of the renin system in adult rat kidneys. Renocortical tissue levels and urinary excretion of PGE2 were reduced to 65 and 40% of control values, respectively, after a single gavage of SC-58236 and did not further decrease on prolonged treatment. Plasma renin activity (PRA) and renin mRNA levels began to decrease after 3 days and reached a constant level of ∼60% of control values after 5 days of treatment. Isoproterenol or left renal artery clipping for 2 days increased PRA and renin mRNA to similar levels in both vehicle- and SC-58236-treated rats after 2 days. Pretreatment with SC-58236 for 5 days, however, reduced the absolute increase in PRA and renin mRNA levels. Notably, the relative increases were not different between vehicle- and SC-58236-treated rats. Similar findings were observed for the stimulation of the renin system by angiotensin II inhibition and low salt intake. These findings indicate that COX-2 inhibition attenuates renin secretion and renin gene expression stimulated by a variety of parameters in proportion to the lowering of basal renin activity, while it does not interfere with the different stimulatory mechanism per se. As a consequence, it appears as if COX-2 activity relevantly determines the set point of the activity of the renin system in rat kidneys.

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The aldo-keto reductase AKR1B7 coexpresses with renin without influencing renin production and secretion

AJP Renal Physiology ◽

10.1152/ajprenal.00617.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. F578-F584 ◽

Cited By ~ 7

Author(s):

Katharina Machura ◽

Elina Iankilevitch ◽

Björn Neubauer ◽

Franz Theuring ◽

Armin Kurtz

Keyword(s):

Enzyme Inhibitor ◽

Plasma Renin ◽

Mrna Levels ◽

Wild Type ◽

Mouse Vas Deferens ◽

Salt Diet ◽

Adult Kidney ◽

Renin Mrna ◽

And Function

On the basis of evidence that within the adult kidney, the aldo-keto reductase AKR1B7 (aldo-keto reductase family 1, member 7, also known as mouse vas deferens protein, MVDP) is selectively expressed in renin-producing cells, we aimed to define a possible role of AKR1B7 for the regulation and function of renin cells in the kidney. We could confirm colocalization and corecruitment of renin and of AKR1B7 in wild-type kidneys. Renin cells in AKR1B7-deficient kidneys showed normal morphology, numbers, and intrarenal distribution. Plasma renin concentration (PRC) and renin mRNA levels of AKR1B7-deficient mice were normal at standard chow and were lowered by a high-salt diet directly comparable to wild-type mice. Treatment with a low-salt diet in combination with an angiotensin-converting enzyme inhibitor strongly increased PRC and renin mRNA in a similar fashion both in AKR1B7-deficient and wild-type mice. Under this condition, we also observed a strong retrograde recruitment of renin-expressing cell along the preglomerular vessels, however, without a difference between AKR1B7-deficient and wild-type mice. The isolated perfused mouse kidney model was used to study the acute regulation of renin secretion by ANG II and by perfusion pressure. Regarding these parameters, no differences were observed between AKR1B7-deficient and wild-type kidneys. In summary, our data suggest that AKR1B7 is not of major relevance for the regulation of renin production and secretion in spite of its striking coregulation with renin expression.

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Abstract 196: Role of Collecting Duct Renin in Blood Pressure Regulation

Hypertension ◽

10.1161/hyp.62.suppl_1.a196 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Nirupama Ramkumar ◽

Deborah Stuart ◽

Sara Rees ◽

Curt Sigmund ◽

Donald E Kohan

Keyword(s):

Blood Pressure ◽

Collecting Duct ◽

Dna Recombination ◽

Plasma Renin ◽

Blood Pressure Regulation ◽

P System ◽

Mrna Levels ◽

Pressure Regulation ◽

Renin Mrna ◽

Exon 1

Recent studies propose that collecting duct (CD) renin is an important modulator of blood pressure regulation, especially in conditions such as angiotensin-II infused hypertension. We used gene targeting to generate a CD-specific renin knockout (KO) to assess if CD derived renin can regulate BP. Utilizing the Cre lox P system, exon 1 of the renin gene was ablated specifically in the CD. BP was recorded via telemetry and plasma and urine were collected in metabolic cages on normal, high and low Na diets. DNA recombination showed kidney specific recombination in KO mice. Compared to floxed mice, CD renin KO mice had 70 % lower medullary renin mRNA levels and 90% lower renin mRNA in micro-dissected cortical and inner medullary CD tubules. Urinary renin levels were significantly lower in the KO mice on normal and low Na diets (45% of floxed levels) but not with high Na intake. Plasma renin concentration was significantly higher in the KO mice on all three diets. While BP was similar between the two groups on all three diets, infusion of Ang-II delayed the increase in BP in the CD renin KO group for at least 4 days post-infusion. These findings suggest that CD renin likely plays a role in normal BP regulation (evidenced by an increase in PRC) and in response to AngII infusion.

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Role of prostanoids in regulation of the renin-angiotensin-aldosterone system by salt intake

AJP Renal Physiology ◽

10.1152/ajprenal.00347.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. F294-F301 ◽

Cited By ~ 38

Author(s):

Klaus Höcherl ◽

Martin C. Kammerl ◽

Karl Schumacher ◽

Dirk Endemann ◽

Horst F. Grobecker ◽

...

Keyword(s):

Plasma Renin Activity ◽

Salt Intake ◽

Plasma Renin ◽

Plasma Aldosterone ◽

Renin Activity ◽

Plasma Aldosterone Concentration ◽

Low Salt ◽

Renin Mrna ◽

Cox 2 ◽

Cox 1

We investigated the effect of cyclooxygenase (COX) activity on the regulation of the renin-angiotensin-aldosterone system by salt intake. Therefore, Sprague-Dawley rats were subjected to different salt diets [0.02, 0.6, and 8% NaCl (wt/wt)] and treated with the selective COX-2 inhibitor rofecoxib (10 mg · kg body wt−1 · day−1) or with ketorolac at a dose selective for COX-1 inhibition (2 mg · kg body wt−1 · day−1) for 3, 7, 14, and 21 days. Rofecoxib and ketorolac caused a similar reduction of renocortical PGE2 formation with a low-salt diet. Rofecoxib did not change plasma renin activity or renocortical renin mRNA abundance with any of the diets but clearly lowered plasma aldosterone concentration. In contrast, ketorolac delayed the increase in plasma renin activity and of renin mRNA in response to low salt intake but did not change plasma aldosterone concentration. Prolonged treatment with rofecoxib but not with ketorolac caused an upregulation of COX-2 expression while COX-1 mRNA abundance remained unchanged. These findings suggest that COX-1-derived, but not COX-2-derived, prostanoids are of relevance for the regulation of the renin system by salt intake.

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Aldosterone enhances renin gene expression in juxtaglomerular cells

AJP Renal Physiology ◽

10.1152/ajprenal.00411.2002 ◽

2004 ◽

Vol 286 (2) ◽

pp. F349-F355 ◽

Cited By ~ 31

Author(s):

Jürgen Klar ◽

Helga Vitzthum ◽

Armin Kurtz

Keyword(s):

Gene Expression ◽

Primary Cultures ◽

Cellular Level ◽

Juxtaglomerular Cells ◽

Mrna Levels ◽

Renin Synthesis ◽

Corticosteroid Hormones ◽

Renin Gene ◽

Renin Mrna ◽

Mrna Half Life

The secretion and synthesis of renin as the key regulator of the renin-angiotensin-aldosterone system are directly controlled by ANG II in the sense of a negative feedback. Because we found that renal afferent arterioles including the juxtaglomerular portion express the mineralocorticoid receptor, we aimed to characterize a possible direct effect of aldosterone on renin synthesis and renin secretion at the level of renal juxtaglomerular cells. Aldosterone (100 nM) clearly enhanced renin mRNA levels in primary cultures of mouse juxtaglomerular cells prestimulated with isoproterenol (100 nM) but had no effect on the exocytosis of stored renin. Similarly, in the mouse juxtaglomerular cell line As4.1, aldosterone time and concentration dependently increased renin mRNA abundance and prorenin secretion up to 2.5-fold. Moreover, aldosterone potentiated cAMP-induced renin gene expression in As4.1 cells. The effect of aldosterone was inhibited by spironolactone and was mimicked by corticosteroid hormones but not by sex steroids. Aldosterone had no influence on basal renin promoter activity but increased the renin mRNA half-life about threefold. In summary, these data suggest that aldosterone exerts a direct positive effect on renin gene expression at the cellular level probably by stabilizing renin mRNA.

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Disruption of the Transmembrane Dense Core Vesicle Proteins IA-2 and IA-2β Causes Female Infertility

Endocrinology ◽

10.1210/en.2005-0638 ◽

2006 ◽

Vol 147 (2) ◽

pp. 811-815 ◽

Cited By ~ 26

Author(s):

Atsutaka Kubosaki ◽

Shinichiro Nakamura ◽

Anne Clark ◽

John F. Morris ◽

Abner L. Notkins

Keyword(s):

Present Report ◽

Female Infertility ◽

Neuroendocrine Cells ◽

Dense Core ◽

Structural Proteins ◽

Corpora Lutea ◽

Dense Core Vesicle ◽

Wild Type ◽

Double Knockout ◽

Female Mice

Female infertility is a worldwide problem affecting 10–15% of the population. The cause of the infertility in many cases is not known. In the present report, we demonstrate that alterations in two transmembrane structural proteins, IA-2 and IA-2β, located in dense core secretory vesicles (DCV) of many endocrine and neuroendocrine cells, can result in female infertility. IA-2 and IA-2β are best known as major autoantigens in type 1 diabetes, but their normal function has remained an enigma. Recently we showed in mice that deletion of IA-2 and/or IA-2β results in impaired insulin secretion and glucose intolerance. We now report that double knockout (DKO), but not single knockout, female mice are essentially infertile. Vaginal smears showed a totally abnormal estrous cycle, and examination of the ovaries revealed normal-appearing oocytes but the absence of corpora lutea. The LH surge that is required for ovulation occurred in wild-type mice but not in DKO mice. Additional studies showed that the LH level in the pituitary of DKO female mice was decreased compared with wild-type mice. Treatment of DKO females with gonadotropins restored corpora lutea formation. In contrast to DKO female mice, DKO male mice were fertile and LH levels in the serum and pituitary were within the normal range. From these studies we conclude that the DCV proteins, IA-2 and IA-2β, play an important role in LH secretion and that alterations in structural proteins of DCV can result in female infertility.

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Dietary salt loading decreases the expressions of neuronal-type nitric oxide synthase and renin in the juxtaglomerular apparatus of angiotensinogen gene-knockout mice.

Journal of the American Society of Nephrology ◽

10.1681/asn.v93355 ◽

1998 ◽

Vol 9 (3) ◽

pp. 355-362

Author(s):

M Kihara ◽

S Umemura ◽

M Yabana ◽

Y Sumida ◽

N Nyui ◽

...

Keyword(s):

Salt Intake ◽

Gene Knockout ◽

Macula Densa ◽

Wild Type ◽

Dietary Salt ◽

Salt Diet ◽

Angiotensinogen Gene ◽

Renin Mrna ◽

Oxide Synthase ◽

Neuronal Type

The present study investigates whether neuronal type nitric oxide synthase (N-NOS) in the macula densa participates in the regulation of renal renin expression during altered dietary salt intake in angiotensinogen gene-knockout (Atg-/-) mice. Wild-type (Atg+/+) and Atg+/+ mice were fed a low-salt (0.04% NaCl), normal-salt (0.3% NaCl), or high-salt (4% NaCl) diet for 2 wk. Histochemical staining for NADPH diaphorase (NADPHd) and renin were analyzed morphometrically. Levels of N-NOS and renin mRNA in renal cortical tissues were determined by reverse transcription-PCR and Northern blot analysis, respectively. In animals fed a normal-salt diet, the renal expressions of N-NOS and renin were markedly increased in Atg-/- mice compared with Atg+/+ mice. When mutant mice were fed a high-salt diet, the signal intensity of the NADPHd reaction and the number of positively stained macula densa cells were significantly decreased. The levels of renal cortical N-NOS mRNA were also suppressed by the treatment. These changes were paralleled by decreases in renal renin-immunoreactive areas and the levels of renin mRNA. On the other hand, salt restriction did not produce further significant increases in the renal N-NOS and renin expressions in mutant mice, whereas a parallel inverse relationship was observed between these enzyme expressions and the levels of salt intake in wild-type mice. These results suggest that the N-NOS expression in the macula densa is inversely regulated by salt intake and that the enzyme activity is functionally linked to renal renin production. Salt-modulated renal N-NOS and renin expressions are independent on angiotensin formation in Atg-/- mice.

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MicroRNA exocytosis by large dense-core vesicle fusion

10.1101/093278 ◽

2016 ◽

Author(s):

Alican Gümürdü ◽

Ramazan Yildiz ◽

Erden Eren ◽

Gökhan Karakülah ◽

Turgay Ünver ◽

...

Keyword(s):

Next Generation Sequencing ◽

Vesicle Fusion ◽

Dense Core ◽

Snare Complex ◽

Dense Core Vesicle ◽

Next Generation ◽

Dense Core Vesicles ◽

Large Dense Core Vesicles ◽

Extracellular Mirna ◽

Generation Sequencing

AbstractNeurotransmitters and peptide hormones are secreted into outside the cell by a vesicle fusion process. Although non-coding RNA (ncRNA) that include microRNA (miRNA) regulates gene expression inside the cell where they are transcribed, extracellular miRNA has been recently discovered outside the cells, proposing that miRNA might be released to participate in cell-to-cell communication. Despite its importance of extracellular miRNA, the molecular mechanisms by which miRNA can be stored in vesicles and released by vesicle fusion remain enigmatic. Using next-generation sequencing, vesicle purification techniques, and synthetic neurotransmission, we observe that large dense-core vesicles (LDCVs) contain a variety of miRNAs including miR-375. Furthermore, miRNA exocytosis is mediated by the SNARE complex and accelerated by Ca2+. Our results suggest that miRNA can be a novel neuromodulator that can be stored in vesicles and released by vesicle fusion together with classical neurotransmitters.One Sentence SummaryUsing next-generation sequencing (NGS) for microRNA (miRNA) and synthetic neurotransmission, we observed that large dense-core vesicles (LDCVs) contain a variety of miRNA together with classical neurotransmitters, and that miRNA can be released by vesicle fusion mediated by SNARE.

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Upregulation of renin-angiotensin system and downregulation of kallikrein in obstructive nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.1993.264.5.f874 ◽

1993 ◽

Vol 264 (5) ◽

pp. F874-F881 ◽

Cited By ~ 13

Author(s):

S. S. el-Dahr ◽

J. Gee ◽

S. Dipp ◽

B. G. Hanss ◽

R. C. Vari ◽

...

Keyword(s):

Renin Angiotensin System ◽

Plasma Renin ◽

Obstructive Nephropathy ◽

Mrna Levels ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Kininase Ii ◽

Plasma Angiotensin ◽

Renin Mrna

The purpose of this study was to delineate the effects of prolonged (1 and 5 wk) unilateral ureteral obstruction (UUO) on the intrarenal renin-angiotensin and kallikrein-kinin systems in the rat. Systolic blood pressure (SBP) and plasma angiotensin (ANG) II levels were significantly higher at 1 and 5 wk of obstruction than in sham-operated groups. Also, plasma renin activity and ANG I levels were elevated at 1 wk (P < 0.05), and plasma angiotensin-converting enzyme (ACE)-kininase II activity was elevated at 5 wk (P < 0.05). Blockade of ANG II receptors with losartan (Dup 753) prevented the rise in SBP after UUO and normalized SBP in chronically hypertensive UUO rats. Renin mRNA levels and ANG II content were elevated in the obstructed kidneys at 1 and 5 wk compared with sham-operated kidneys (P < 0.05). ACE-kininase II activity was elevated in both the obstructed and contralateral kidneys at 5 wk compared with sham-operated kidneys (P < 0.05). In marked contrast to renin, total immunoreactive kallikrein contents and tissue kallikrein mRNA levels in the obstructed kidneys were reduced to 25% of sham-operated kidneys both at 1 and 5 wk (P < 0.001). The results indicate that urinary obstruction activates renin and suppresses kallikrein gene expression. Activation of ACE-kininase II by UUO also serves to enhance intrarenal ANG II generation and kinin degradation. The results implicate ANG II overproduction and kinin deficiency in the pathogenesis of UUO-induced hypertension and intrarenal vasoconstriction.

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