scholarly journals 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

2017 ◽  
Vol 234 (1) ◽  
pp. T35-T47 ◽  
Author(s):  
Shigeru Shibata

A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K+ homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K+ secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K+ alterations, regulating Na–Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high-aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron.

2019 ◽  
Vol 133 (1) ◽  
pp. 75-82
Author(s):  
Osamu Yamazaki ◽  
Kenichi Ishizawa ◽  
Daigoro Hirohama ◽  
Toshiro Fujita ◽  
Shigeru Shibata

Abstract Distal nephron of the kidney plays key roles in fluid volume and electrolyte homeostasis by tightly regulating reabsorption and excretion of Na+, K+, and Cl−. Studies to date demonstrate the detailed electrolyte transport mechanisms in principal cells of the cortical collecting duct, and their regulation by renin–angiotensin–aldosterone system (RAAS). In recent years, however, accumulating data indicate that intercalated cells, another cell type that is present in the cortical collecting duct, also play active roles in the regulation of blood pressure. Notably, pendrin in β-intercalated cells not only controls acid/base homeostasis, but is also one of the key components controlling salt and K+ transport in distal nephron. We have recently shown that pendrin is regulated by the co-ordinated action of angiotensin II (AngII) and aldosterone, and at the downstream of AngII, mammalian target of rapamycin (mTOR) signaling regulates pendrin through inhibiting the kinase unc51-like-kinase 1 and promoting dephosphorylation of mineralocorticoid receptor (MR). In this review, we summarize recent advances in the current knowledge on the salt transport mechanisms in the cortical collecting duct, and their regulation by the RAAS.


2013 ◽  
Vol 305 (5) ◽  
pp. F701-F713 ◽  
Author(s):  
Jill W. Verlander ◽  
Diana Chu ◽  
Hyun-Wook Lee ◽  
Mary E. Handlogten ◽  
I. David Weiner

Renal glutamine synthetase catalyzes the reaction of NH4+ with glutamate, forming glutamine and decreasing the ammonia available for net acid excretion. The purpose of the present study was to determine glutamine synthetase's specific cellular expression in the mouse kidney and its regulation by hypokalemia, a common cause of altered renal ammonia metabolism. Glutamine synthetase mRNA and protein were present in the renal cortex and in both the outer and inner stripes of the outer medulla. Immunohistochemistry showed glutamine synthetase expression throughout the entire proximal tubule and in nonproximal tubule cells. Double immunolabel with cell-specific markers demonstrated glutamine synthetase expression in type A intercalated cells, non-A, non-B intercalated cells, and distal convoluted tubule cells, but not in principal cells, type B intercalated cells, or connecting segment cells. Hypokalemia induced by feeding a nominally K+-free diet for 12 days decreased glutamine synthetase expression throughout the entire proximal tubule and in the distal convoluted tubule and simultaneously increased glutamine synthetase expression in type A intercalated cells in both the cortical and outer medullary collecting duct. We conclude that glutamine synthetase is widely and specifically expressed in renal epithelial cells and that the regulation of expression differs in specific cell populations. Glutamine synthetase is likely to mediate an important role in renal ammonia metabolism.


2020 ◽  
Author(s):  
Guanghui Xu ◽  
Yuhao Wang ◽  
Hushan Zhang ◽  
Xueke She ◽  
Jianjun Yang

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.


2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.


Angiogenesis ◽  
2021 ◽  
Author(s):  
Corina Marziano ◽  
Gael Genet ◽  
Karen K. Hirschi

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.


Author(s):  
Luigi Montano ◽  
Francesco Donato ◽  
Pietro Massimiliano Bianco ◽  
Gennaro Lettieri ◽  
Antonino Guglielmino ◽  
...  

AbstractThe epidemic of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted worldwide with its infectious spread and mortality rate. Thousands of articles have been published to tackle this crisis and many of these have indicated that high air pollution levels may be a contributing factor to high outbreak rates of COVID-19. Atmospheric pollutants, indeed, producing oxidative stress, inflammation, immuno-unbalance, and systemic coagulation, may be a possible significant co-factor of further damage, rendering the body prone to infections by a variety of pathogens, including viruses. Spermatozoa are extremely responsive to prooxidative effects produced by environmental pollutants and may serve as a powerful alert that signals the extent that environmental pressure, in a specific area, is doing damage to humans. In order to improve our current knowledge on this topic, this review article summarizes the relevant current observations emphasizing the weight that environmental pollution has on the sensitivity of a given population to several diseases and how semen quality, may be a potential indicator of sensitivity for virus insults (including SARS-CoV-2) in high polluted areas, and help to predict the risk for harmful effects of the SARS-CoV-2 epidemic. In addition, this review focused on the potential routes of virus transmission that may represent a population health risk and also identified the areas of critical importance that require urgent research to assess and manage the COVID-19 outbreak.


1964 ◽  
Vol 37 (5) ◽  
pp. 1245-1298 ◽  
Author(s):  
F. A. Heckman

Abstract Although the microstructure of carbon black has been under investigation for more than fifty years, there are still many aspects which are controversial and some which are virtually unexplored. The inherently low degree of crystallinity and the finely-divided state of carbon blacks have greatly hindered efforts to understand them. The purpose of this article is to cite the principal contributors to our understanding of carbon black microstructure, to discuss the significance of their contribution, to present a clear picture of the present state of our knowledge, and to note areas where controversy exists and where our knowledge is incomplete. The scope of this article is necessarily limited to a reasonably complete treatment of the several aspects of carbon black microstructure; that is, the arrangement of carbon atoms to form graphite layer planes, the arrangement of layer planes to form crystallites, and the arrangement of crystallites to form the more familiar carbon black “particles” or aggregates. Particular attention is paid to more recent articles and those which have shaped our thinking on carbon black microstructure. This article also includes a fairly complete review of various studies on the changes in microstructure which are brought about by heat treatment or oxidation. In general, the rather large number of studies reporting on the microstructure of other forms of carbon have not been reviewed (except for the work of Franklin whose contribution to our understanding of carbon-black microstructure is so immense that it must be included). Although gross, morphological features such as particle size, primary aggregate size and shape are studied briefly in order to relate them to microstructure, no effort was made to review comprehensively the body of literature pertinent to this subject. Also porosity and surface characteristics per se (as measured by gas adsorption techniques) are not treated in detail here. Rather than review a dreary list of papers which have only the slightest bearing on carbon black, the author has taken the liberty of dividing the articles reviewed into two categories. The first category, which is reviewed in some detail, includes those publications in which an important contribution was made to the understanding of carbon-black microstructure. The second category includes all those articles which are discussed only briefly or not at all because the authors have reported superficial or routine studies or they (probably unknown to them) have essentially duplicated the work of an earlier worker, or have reported uncorrected results which are thus so inaccurate as to be without real value to this article; or because they comprise work which is only peripherally related to carbon black microstructure. Also, references taken from other papers, but not reviewed here, are included in the latter category. Articles by Warren, Hofmann and Wilm, Steward and Cook and Walker contain bibliographies which will be helpful to those interested in the earlier work or in the microstructure of carbons other than carbon black. For the reader whose time is limited, an adequate picture of current understanding of carbon black microstructure can be gained by reading Sections II, IV, and V which are relatively short. Finally, a word about the spirit in which the review was written. At the request of the late Dr. Craig, a critical review was prepared in which every effort was made to point out shortcomings as well as classic contributions contained in the pertinent literature. Where the experts have disagreed, the reviewer, often with skill unequal to the task, has attempted to decide which one was the more correct in the light of current knowledge. It is with deep humility and great respect for those who have gone before that this review is submitted.


2021 ◽  
pp. 1-16
Author(s):  
Marcin Adamczak ◽  
Stanisław Surma

<b><i>Background:</i></b> Metabolic acidosis in CKD is diagnosed in patients with plasma or venous blood bicarbonate concentration lower than 22 mmol/L. Metabolic acidosis occurs in about 20% of patients with CKD. Metabolic acidosis may lead to dysfunction of many systems and organs as well as CKD progression. Currently, sodium bicarbonate is mainly used for pharmacological treatment of metabolic acidosis in patients with CKD. Veverimer is a new drug dedicated to treatment of metabolic acidosis in patients with CKD. Orally given veverimer binds hydrogen ions in the intestines and subsequently is excreted from the body with feces. Clinical studies have shown that veverimer is effective in increasing serum bicarbonate concentrations in CKD patients with metabolic acidosis. Here, we present review of the epidemiology, pathogenesis, diagnosis, treatment, and prevention of metabolic acidosis in CKD patients. <b><i>Summary:</i></b> Metabolic acidosis is common in patients with CKD and contributes to CKD progression and many complications, which worsen the prognosis in these patients. Currently, sodium bicarbonate is mainly used in metabolic acidosis treatment. The role of the new drug veverimer in the metabolic acidosis therapy needs further studies. <b><i>Key Message:</i></b> The aim of this review article is to summarize the current knowledge concerning the epidemiology, pathogenesis, diagnosis, treatment, and prevention of metabolic acidosis in CKD patients.


2011 ◽  
Vol 43 (14) ◽  
pp. 884-894 ◽  
Author(s):  
Miyuki Matsuda ◽  
Kouichi Tamura ◽  
Hiromichi Wakui ◽  
Toru Dejima ◽  
Akinobu Maeda ◽  
...  

We previously cloned a molecule that interacts with angiotensin II type 1 (AT1) receptor to exert an inhibitory function on AT1 receptor signaling that we named ATRAP/ Agtrap (for AT1 receptor-associated protein). In the present study we examined the regulation of basal ATRAP gene expression using renal distal convoluted tubule cells. We found that serum starvation upregulated basal expression of ATRAP gene, a response that required de novo mRNA and protein synthesis. Luciferase assay revealed that the proximal promoter region directs transcription and that a putative binding site of runt-related transcription factors (RBE) is important for transcriptional activation. The results of RBE-decoy transfection and endogenous knockdown by small interference RNA showed that the runt-related transcription factor Runx3 is involved in ATRAP gene expression. Chromatin immunoprecipitation assay also supported the binding of Runx3 to the ATRAP promoter in renal distal convoluted tubule cells. Immunohistochemistry demonstrated the expression of Runx3 and ATRAP proteins in the distal convoluted and connecting tubules of the kidney in consecutive sections. Furthermore, the Runx3 immunostaining was decreased together with a concomitant suppression of ATRAP expression in the affected kidney after 7 days of unilateral ureteral obstruction. These findings indicate that Runx3 plays a role in ATRAP gene expression in renal distal tubular cells both in vitro and in vivo.


Sign in / Sign up

Export Citation Format

Share Document