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American Journal of Physiology. Renal... Jan 2010Renin is the enzyme which is the rate-limiting step in the formation of the hormone angiotensin II. Therefore, the regulation of renin secretion is critical in... (Review)
Review
Renin is the enzyme which is the rate-limiting step in the formation of the hormone angiotensin II. Therefore, the regulation of renin secretion is critical in understanding the control of the renin-angiotensin-aldosterone system and its many biological and pathological actions. Renin is synthesized, stored in, and released from the juxtaglomerular (JG) cells of the kidney. While renin secretion is positively regulated by the "second messenger" cAMP, unlike most secretory cells, renin secretion from the JG cell is inversely related to the extracellular and intracellular calcium concentrations. This novel relationship is referred to as the "calcium paradox." This review will address observations made over the past 30 years regarding calcium and the regulation of renin secretion, and focus on recent observations which address this scientific conundrum. These include 1) receptor-mediated pathways for changing intracellular calcium; 2) the discovery of a calcium-inhibitable isoform of adenylyl cyclase associated with renin in the JG cells; 3) calcium-sensing receptors in the JG cells; 4) calcium-calmodulin-mediated signals; 5) the role of phosphodiesterases; and 6) connexins, gap junctions, calcium waves, and the cortical extracellular calcium environment. While cAMP is the dominant second messenger for renin secretion, calcium appears to modulate the integrated activities of the enzymes, which balance cAMP synthesis and degradation. Thus this review concludes that calcium modifies the amplitude of cAMP-mediated renin-signaling pathways. While calcium does not directly control renin secretion, increased calcium inhibits and decreased calcium amplifies cAMP-stimulated renin secretion.
Topics: Animals; Calcium; Cyclic AMP; Humans; Juxtaglomerular Apparatus; Renin; Renin-Angiotensin System; Signal Transduction
PubMed: 19640903
DOI: 10.1152/ajprenal.00143.2009 -
American Journal of Physiology. Renal... Nov 2014The Na-K-2Cl cotransporter (NKCC2; BSC1) is located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL). NKCC2... (Review)
Review
The Na-K-2Cl cotransporter (NKCC2; BSC1) is located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL). NKCC2 facilitates ∼20-25% of the reuptake of the total filtered NaCl load. NKCC2 is therefore one of the transport proteins with the highest overall reabsorptive capacity in the kidney. Consequently, even subtle changes in NKCC2 transport activity considerably alter the renal reabsorptive capacity for NaCl and eventually lead to perturbations of the salt and water homoeostasis. In addition to facilitating the bulk reabsorption of NaCl in the TAL, NKCC2 transport activity in the macula densa cells of the TAL constitutes the initial step of the tubular-vascular communication within the juxtaglomerular apparatus (JGA); this communications allows the TAL to modulate the preglomerular resistance of the afferent arteriole and the renin secretion from the granular cells of the JGA. This review provides an overview of our current knowledge with respect to the general functions of NKCC2, the modulation of its transport activity by different regulatory mechanisms, and new developments in the pathophysiology of NKCC2-dependent renal NaCl transport.
Topics: Alternative Splicing; Animals; Bartter Syndrome; Gene Expression Regulation; Humans; Kidney; Loop of Henle; Mice; Protein Isoforms; Solute Carrier Family 12, Member 1
PubMed: 25186299
DOI: 10.1152/ajprenal.00432.2014 -
Vascular Health and Risk Management 2016SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM). These agents target the kidney to promote urinary glucose excretion,... (Review)
Review
SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM). These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP) lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin) on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin-angiotensin-aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose control.
Topics: Animals; Antihypertensive Agents; Benzhydryl Compounds; Biomarkers; Blood Glucose; Blood Pressure; Canagliflozin; Comorbidity; Diabetes Mellitus, Type 2; Glucosides; Humans; Hypertension; Hypoglycemic Agents; Kidney; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome
PubMed: 27822054
DOI: 10.2147/VHRM.S111991 -
Kidney International. Supplement Sep 1998The juxtaglomerular apparatus (JGA) is composed of the macula densa (MD), the extraglomerular mesangium, and the juxtaglomerular arterioles. The JGA functions to adapt... (Review)
Review
The juxtaglomerular apparatus (JGA) is composed of the macula densa (MD), the extraglomerular mesangium, and the juxtaglomerular arterioles. The JGA functions to adapt glomerular filtration rate (GFR) to distal tubular [NaCl] and to adjust the synthesis and release of renin. The type 1 isoform of nitric oxide synthase (NOS1) is present in MD cells, and release of NO toward the glomerular vasculature is thought to modulate signaling at the JGA. Chronic alterations in GFR and/or tubular [NaCl] are paralleled by adjustments of NOS1. Molecular characterization of NOS1 mRNA reveals several renal variants suggesting cell type-specific regulation at the level of transcription and translation.
Topics: Animals; Juxtaglomerular Apparatus; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II
PubMed: 9736249
DOI: 10.1046/j.1523-1755.1998.06706.x -
American Journal of Physiology.... Sep 2014Little is known about the molecular mechanism mediating renin granule exocytosis and the identity of proteins involved. We previously showed that soluble... (Review)
Review
Little is known about the molecular mechanism mediating renin granule exocytosis and the identity of proteins involved. We previously showed that soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNAREs), a family of proteins required for exocytosis, mediate the stimulated release of renin from juxtaglomerular cells. This minireview focuses on the current knowledge of the proteins that facilitate renin-granule exocytosis. We discuss the identity of potential candidates that mediate the signaling and final steps of exocytosis of the renin granule.
Topics: Animals; Exocytosis; Humans; Juxtaglomerular Apparatus; Membrane Fusion; Renin; SNARE Proteins; Signal Transduction
PubMed: 24944251
DOI: 10.1152/ajpregu.00175.2014 -
Current Urology Sep 2019Juxtaglomerular cell tumor (JGCT), or reninoma, is a typically benign neoplasm generally affecting adolescents and young adults due to modified smooth muscle cells from... (Review)
Review
Juxtaglomerular cell tumor (JGCT), or reninoma, is a typically benign neoplasm generally affecting adolescents and young adults due to modified smooth muscle cells from the afferent arteriole of the juxtaglomerular apparatus. Patients experience symptoms related to hypertension and hypoka-lemia due to renin-secretion by the tumor. MRI, PET, CT, and renal vein catheterizations can be used to capture JGCTs, with laparoscopic ultrasonography being most cost-efective. Surgical removal is the best option for management; electrolyte imbalances are a potential complication which may be assuaged via pre-surgical administration of aliskiren, a renin inhibitor. Considering the vast etiology for hypertension and rarity of JGCT, the diagnosing physician must have a high index of suspicion for JGCT. Early recognition and management can help prevent cardiovascular or pregnancy complications and fatalities, vascular invasion and metastasis, improve quality of life, and limit socioeconomic liabilities. Herein we review the epidemiology, genetics, histopathol-ogy, clinical presentation, and management of this rare condition. The impact of genetics on prognosis warrant further research.
PubMed: 31579192
DOI: 10.1159/000499301 -
American Journal of Physiology. Renal... Mar 2021
Topics: Juxtaglomerular Apparatus; Kidney Tubules; Sodium Chloride, Dietary
PubMed: 33586498
DOI: 10.1152/ajprenal.00051.2021 -
CEN Case Reports Nov 2015Juxtaglomerular apparatus (JGA) hyperplasia rarely happened in renal biopsy and has been controversial clinically, because synthesis and secretion of renin were...
Juxtaglomerular apparatus (JGA) hyperplasia rarely happened in renal biopsy and has been controversial clinically, because synthesis and secretion of renin were susceptible to the effect of clinical condition and medication. Here we present the case of a 39-year-old who got JGA hyperplasia of IgA nephropathy (IgAN) after long-term inhibition of the renin-angiotensin system (RAS) with an angiotensin receptor blocker (ARB), and a direct renin inhibitor (DRI) in combination with a diuretic. He was diagnosed with IgAN in his first renal biopsy, and was treated with supra-maximal dosages of ARB, DRI and a diuretic. In the second biopsy, because of the massive proteinuria and occurrence of steroid-induced diabetes, it was revealed that the area and the number of JGA cells were strikingly increased in observed glomeruli. Immunohistopathologically, the both specimens were stained by human renin antibody. The hyperplastic JG cells contained a large amount of renin granules. Putative renin granules were observed in some interstitial cells adjacent to an afferent arteriole by electron microscopy. The increasing response of renin granules co-localized in prominent JGA hyperplasia should be worried while physicians treat hypertensive patients with potent RAS inhibitors and diuretics even though they have diabetes. This is the first report showing a clinical course of forming prominent JGA hyperplasia directly after a full combination of RAS inhibitors and diuretics in adult IgA nephropathy.
PubMed: 28509110
DOI: 10.1007/s13730-015-0177-y -
Scientific Reports Mar 2022The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular...
The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular filtration and renin release. However, details of mechanosensory systems in these cells are unclear. Piezo2 is a recently identified mechanically activated ion channel found in various tissues, especially sensory neurons. Herein, we examined Piezo2 expression and regulation in mouse kidneys. RNAscope in situ hybridization revealed that Piezo2 expression was highly localized in mesangial cells and juxtaglomerular renin-producing cells. Immunofluorescence assays detected GFP signals in mesangial cells and juxtaglomerular renin-producing cells of Piezo2 reporter mice. Piezo2 transcripts were observed in the Foxd1-positive stromal progenitor cells of the metanephric mesenchyme in the developing mouse kidney, which are precursors of mesangial cells and renin-producing cells. In a mouse model of dehydration, Piezo2 expression was downregulated in mesangial cells and upregulated in juxtaglomerular renin-producing cells, along with the overproduction of renin and enlargement of the area of renin-producing cells. Furthermore, the expression of the renin coding gene Ren1 was reduced by Piezo2 knockdown in cultured juxtaglomerular As4.1 cells under static and stretched conditions. These data suggest pivotal roles for Piezo2 in the regulation of glomerular filtration and body fluid balance.
Topics: Animals; Ion Channels; Juxtaglomerular Apparatus; Kidney; Mesangial Cells; Mice; Renin
PubMed: 35273307
DOI: 10.1038/s41598-022-07987-7 -
Physiological Reviews Oct 2011The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their... (Review)
Review
The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane "hemi-channels," for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.
Topics: Animals; Cell Communication; Connexins; Endocrine System; Humans; Insulin-Secreting Cells; Juxtaglomerular Apparatus; Gap Junction alpha-5 Protein; Gap Junction delta-2 Protein
PubMed: 22013215
DOI: 10.1152/physrev.00027.2010