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International Journal of Molecular... Oct 2022In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na and water reabsorption in... (Review)
Review
In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na coupled with glucose and can restore renal O demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36233288
DOI: 10.3390/ijms231911987 -
Hypertension (Dallas, Tex. : 1979) Mar 2017Although renin cells are crucial for blood pressure homeostasis, little is known about their nature. We now know that renin cells are precursors that appear early and in... (Review)
Review
Although renin cells are crucial for blood pressure homeostasis, little is known about their nature. We now know that renin cells are precursors that appear early and in multiple tissues during embryonic development. They participate in morphogenetic events, vascular development and injury, tissue repair and regeneration. When confronted to a homeostatic threat, renin cell descendants have the capability to switch the renin gene on or off. This poorly understood switch or molecular memory enables the organism to maintain constancy of the internal milieu and tissue perfussion. Here, we discuss briefly the major events that govern the acquisition and maintenace of renin cell identity and how manipulations that alter the fate of renin cells can lead to serious disease. We also advance the concept that renin cells are at the center of an ancestral sytem of defense linking the endocrine, the immune and repair responses of the organism.
Topics: Animals; Humans; Juxtaglomerular Apparatus; Kidney; Renin; Renin-Angiotensin System
PubMed: 28137982
DOI: 10.1161/HYPERTENSIONAHA.116.08316 -
The Journal of Clinical Investigation Jun 2024The macula densa (MD) is a distinct cluster of approximately 20 specialized kidney epithelial cells that constitute a key component of the juxtaglomerular apparatus....
The macula densa (MD) is a distinct cluster of approximately 20 specialized kidney epithelial cells that constitute a key component of the juxtaglomerular apparatus. Unlike other renal tubular epithelial cell populations with functions relating to reclamation or secretion of electrolytes and solutes, the MD acts as a cell sensor, exerting homeostatic actions in response to sodium and chloride changes within the tubular fluid. Electrolyte flux through apical sodium transporters in MD cells triggers release of paracrine mediators, affecting blood pressure and glomerular hemodynamics. In this issue of the JCI, Gyarmati and authors explored a program of MD that resulted in activation of regeneration pathways. Notably, regeneration was triggered by feeding mice a low-salt diet. Furthermore, the MD cells showed neuron-like properties that may contribute to their regulation of glomerular structure and function. These findings suggest that dietary sodium restriction and/or targeting MD signaling might attenuate glomerular injury.
Topics: Animals; Regeneration; Mice; Kidney; Humans; Diet, Sodium-Restricted; Juxtaglomerular Apparatus; Sodium Chloride, Dietary; Signal Transduction; Kidney Glomerulus
PubMed: 38828728
DOI: 10.1172/JCI181397 -
Nutrients Feb 2022For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as... (Review)
Review
For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as the situation demands by the juxtaglomerular cells (also called as granular cells) that are in the walls of the afferent arterioles. Juxtaglomerular cells can sense minute changes in the blood pressure and blood volume and accordingly synthesize, store, and secrete appropriate amounts of renin. Thus, when the blood pressure and blood volume are decreased JGA cells synthesize and secrete higher amounts of renin and when the blood pressure and blood volume is increased the synthesis and secretion of renin is decreased such that homeostasis is restored. To decipher this important function, JGA cells (renin cells) need to sense and transmit the extracellular physical forces to their chromatin to control renin gene expression for appropriate renin synthesis. The changes in perfusion pressure are sensed by Integrin β1 that is transmitted to the renin cell's nucleus via lamin A/C that produces changes in the architecture of the chromatin. This results in an alteration (either increase or decrease) in renin gene expression. Cell membrane is situated in an unique location since all stimuli need to be transmitted to the cell nucleus and messages from the DNA to the cell external environment can be conveyed only through it. This implies that cell membrane structure and integrity is essential for all cellular functions. Cell membrane is composed to proteins and lipids. The lipid components of the cell membrane regulate its (cell membrane) fluidity and the way the messages are transmitted between the cell and its environment. Of all the lipids present in the membrane, arachidonic acid (AA) forms an important constituent. In response to pressure and other stimuli, cellular and nuclear shape changes occur that render nucleus to act as an elastic mechanotransducer that produces not only changes in cell shape but also in its dynamic behavior. Cell shape changes in response to external pressure(s) result(s) in the activation of cPLA2 (cytosolic phospholipase 2)-AA pathway that stretches to recruit myosin II which produces actin-myosin cytoskeleton contractility. Released AA can undergo peroxidation and peroxidized AA binds to DNA to regulate the expression of several genes. Alterations in the perfusion pressure in the afferent arterioles produces parallel changes in the renin cell membrane leading to changes in renin release. AA and its metabolic products regulate not only the release of renin but also changes in the vanilloid type 1 (TRPV1) expression in renal sensory nerves. Thus, AA and its metabolites function as intermediate/mediator molecules in transducing changes in perfusion and mechanical pressures that involves nuclear mechanotransduction mechanism. This mechanotransducer function of AA has relevance to the synthesis and release of insulin, neurotransmitters, and other soluble mediators release by specialized and non-specialized cells. Thus, AA plays a critical role in diseases such as diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, sepsis, lupus, rheumatoid arthritis, and cancer.
Topics: Arachidonic Acid; Juxtaglomerular Apparatus; Mechanotransduction, Cellular; Pressoreceptors; Renin
PubMed: 35215399
DOI: 10.3390/nu14040749 -
International Journal of Molecular... Nov 2020Our study analyzed the expression pattern of different connexins (Cxs) and renin positive cells in the juxtaglomerular apparatus (JGA) of developing, postnatal healthy...
Our study analyzed the expression pattern of different connexins (Cxs) and renin positive cells in the juxtaglomerular apparatus (JGA) of developing, postnatal healthy human kidneys and in nephrotic syndrome of the Finnish type (CNF), by using double immunofluorescence, electron microscopy and statistical measuring. The JGA contained several cell types connected by Cxs, and consisting of macula densa, extraglomerular mesangium (EM) and juxtaglomerular cells (JC), which release renin involved in renin-angiotensin- aldosteron system (RAS) of arterial blood pressure control. During JGA development, strong Cx40 expression gradually decreased, while expression of Cx37, Cx43 and Cx45 increased, postnatally showing more equalized expression patterning. In parallel, initially dispersed renin cells localized to JGA, and greatly increased expression in postnatal kidneys. In CNF kidneys, increased levels of Cx43, Cx37 and Cx45 co-localized with accumulations of renin cells in JGA. Additionally, they reappeared in extraglomerular mesangial cells, indicating association between return to embryonic Cxs patterning and pathologically changed kidney tissue. Based on the described Cxs and renin expression patterning, we suggest involvement of Cx40 primarily in the formation of JGA in developing kidneys, while Cx37, Cx43 and Cx45 might participate in JGA signal transfer important for postnatal maintenance of kidney function and blood pressure control.
Topics: Child; Connexin 43; Connexins; Female; Fetus; Gap Junctions; Humans; Infant; Juxtaglomerular Apparatus; Kidney; Kidney Tubules; Male; Myocytes, Smooth Muscle; Nephrotic Syndrome; Renin; Renin-Angiotensin System; Signal Transduction; Gap Junction alpha-5 Protein; Gap Junction alpha-4 Protein
PubMed: 33172216
DOI: 10.3390/ijms21218349 -
Expert Opinion on Pharmacotherapy May 2024Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney... (Review)
Review
INTRODUCTION
Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD).
AREA COVERED
JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs.
EXPERT OPINION
When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb.The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD.
Topics: Humans; Homeostasis; Renal Insufficiency, Chronic; Animals; Juxtaglomerular Apparatus; Sodium-Glucose Transporter 2 Inhibitors; Tolvaptan; Disease Progression; Polycystic Kidney, Autosomal Dominant; Renin-Angiotensin System; Sodium; Antidiuretic Hormone Receptor Antagonists
PubMed: 38773961
DOI: 10.1080/14656566.2024.2357188 -
Hypertension (Dallas, Tex. : 1979) Feb 2020Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as...
Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.
Topics: Aging; Animals; Blood Pressure; Disease Models, Animal; Glomerular Filtration Rate; Homeostasis; Hypertension; Kidney; Male; Mice; Mice, Inbred C57BL; Renal Circulation; Vasoconstriction
PubMed: 31838907
DOI: 10.1161/HYPERTENSIONAHA.119.13588 -
International Journal of Nephrology and... 2020Glomerular filtration rate is controlled by the contractile effect of angiotensin II on afferent and efferent arterioles. The renin positivity of the afferent arterioles... (Review)
Review
Glomerular filtration rate is controlled by the contractile effect of angiotensin II on afferent and efferent arterioles. The renin positivity of the afferent arterioles depends on tubuloglomerular feedback via the macula densa (MD) and short loop feedback via the afferent arteriolar endothelia. The renin-producing cells are trans-differentiated from smooth muscle cells (SMCs) of mainly the afferent arterioles, the MD cells are trans-differentiated from the neighboring tubular cells, and the high-permeability endothelial cells are trans-differentiated from normal permeability endothelial cells facing the renin-negative part of the afferent arterioles. All of the trans-differentiations depend on the activity of the renin-angiotensin system (RAS). The distribution of AT1 receptors for angiotensin II expresses the contractile effects of angiotensin II on renin-negative SMCs and the negative effect on trans-differentiation of renin-positive SMCs and MD cells. The purpose of this review is to summarize the stereological data of molecules like angiotensin II AT1 receptors, L-type calcium channels, and renin receptors in the juxtaglomerular apparatus of normal and STZ-induced diabetic rat kidneys, thus showing their functional relevancies on trans-differentiation among the juxtaglomerular apparatus' elements.
PubMed: 32606889
DOI: 10.2147/IJNRD.S246476 -
Revista Da Associacao Medica Brasileira... Jan 2020Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for... (Review)
Review
Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.
Topics: Benzhydryl Compounds; Canagliflozin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glomerular Filtration Rate; Glucose; Glucosides; Humans; Hypoglycemic Agents; Kidney; Kidney Diseases; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 31939531
DOI: 10.1590/1806-9282.66.S1.17 -
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