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European Endocrinology Oct 2020Therapeutic advances have revolutionised cancer treatment over the last two decades, but despite improved survival and outcomes, adverse effects to anticancer therapy... (Review)
Review
Therapeutic advances have revolutionised cancer treatment over the last two decades, but despite improved survival and outcomes, adverse effects to anticancer therapy such as dyselectrolytaemias do occur and need to be managed appropriately. This review explores essential aspects of sodium homeostasis in cancer with a focus on alterations arising from anticancer medications. Sodium and water balance are tightly regulated by close interplay of stimuli arising from hypothalamic osmoreceptors, arterial and atrial baroreceptors and the renal juxtaglomerular apparatus. This delicate balance can be disrupted by cancer itself, as well as the medications used to treat it. Some of the conventional chemotherapeutics, such as alkylating agents and platinum-based drugs, can cause hyponatraemia and, on rare occasions, hypernatraemia. Other conventional agents such as vinca alkaloids, as well as newer targeted cancer therapies including small molecule inhibitors and monoclonal antibodies, can cause hyponatraemia, usually as a result of inappropriate antidiuretic hormone secretion. Hyponatraemia can also sometimes occur secondarily to drug-induced hypocortisolism or salt-wasting syndromes. Another atypical but distinct mechanism for hyponatraemia is via pituitary dysfunction induced by immune checkpoint inhibitors. Hypernatraemia is uncommon and occasionally ensues as a result of drug-induced nephrogenic diabetes insipidus. Identification of the aetiology and appropriate management of these conditions, in addition to averting treatment-related problems, can be lifesaving in critical situations.
PubMed: 33117443
DOI: 10.17925/EE.2020.16.2.122 -
High Blood Pressure & Cardiovascular... Sep 2017Renin is the first and rate-limiting step of the renin-angiotensin system. The exclusive source of renin in the circulation are the juxtaglomerular cells of the kidney,... (Review)
Review
Renin is the first and rate-limiting step of the renin-angiotensin system. The exclusive source of renin in the circulation are the juxtaglomerular cells of the kidney, which line the afferent arterioles at the entrance of the glomeruli. Normally, renin production by these cells suffices to maintain homeostasis. However, under chronic stimulation of renin release, for instance during a low-salt diet or antihypertensive therapy, cells that previously expressed renin during congenital life re-convert to a renin-producing cell phenotype, a phenomenon which is known as "recruitment". How exactly such differentiation occurs remains to be clarified. This review critically discusses the phenotypic plasticity of renin cells, connecting them not only to the classical concept of blood pressure regulation, but also to more complex contexts such as development and growth processes, cell repair mechanisms and tissue regeneration.
Topics: Animals; Calcium Signaling; Cardiovascular Diseases; Cell Plasticity; Cyclic AMP; Cyclic GMP; Embryonic Stem Cells; Epigenesis, Genetic; Humans; Juxtaglomerular Apparatus; Kidney Diseases; Phenotype; Regeneration; Renin-Angiotensin System; Second Messenger Systems
PubMed: 28527017
DOI: 10.1007/s40292-017-0212-5 -
Nature Communications Sep 2023Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet...
Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.
Topics: Humans; Renin; Kidney Neoplasms; Juxtaglomerular Apparatus; Kidney Glomerulus; Signal Transduction; Receptor, Notch1
PubMed: 37749094
DOI: 10.1038/s41467-023-41118-8 -
Physiology (Bethesda, Md.) Oct 2007The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure... (Review)
Review
The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure homeostasis of the body. Renin is mainly produced and released into circulation by the so-called juxtaglomerular epithelioid cells, located in the walls of renal afferent arterioles at the entrance of the glomerular capillary network. It has been known for a long time that renin synthesis and secretion are stimulated by the sympathetic nerves and the prostaglandins and are inhibited in negative feedback loops by angiotensin II, high blood pressure, salt, and volume overload. In contrast, the events controlling the function of renin-secreting cells at the organ and cellular level are markedly less clear and remain mysterious in certain aspects. The unravelling of these mysteries has led to new and interesting insights into the process of renin release.
Topics: Animals; Cyclic AMP; Humans; Juxtaglomerular Apparatus; Kidney; Paracrine Communication; Protein Processing, Post-Translational; Renin; Secretory Vesicles; Signal Transduction
PubMed: 17928544
DOI: 10.1152/physiol.00024.2007 -
Circulation Research Apr 2021Renin cells are essential for survival perfected throughout evolution to ensure normal development and defend the organism against a variety of homeostatic threats.... (Review)
Review
Renin cells are essential for survival perfected throughout evolution to ensure normal development and defend the organism against a variety of homeostatic threats. During embryonic and early postnatal life, they are progenitors that participate in the morphogenesis of the renal arterial tree. In adult life, they are capable of regenerating injured glomeruli, control blood pressure, fluid-electrolyte balance, tissue perfusion, and in turn, the delivery of oxygen and nutrients to cells. Throughout life, renin cell descendants retain the plasticity or memory to regain the renin phenotype when homeostasis is threatened. To perform all of these functions and maintain well-being, renin cells must regulate their identity and fate. Here, we review the major mechanisms that control the differentiation and fate of renin cells, the chromatin events that control the memory of the renin phenotype, and the major pathways that determine their plasticity. We also examine how chronic stimulation of renin cells alters their fate leading to the development of a severe and concentric hypertrophy of the intrarenal arteries and arterioles. Lastly, we provide examples of additional changes in renin cell fate that contribute to equally severe kidney disorders.
Topics: Animals; Arterioles; Blood Pressure; Cell Communication; Cell Differentiation; Cell Plasticity; Chromatin; Chromatin Assembly and Disassembly; Connexins; Homeostasis; Humans; Hypertension; Integrins; Juxtaglomerular Apparatus; Kidney; Kidney Glomerulus; Mice; MicroRNAs; Phenotype; Regeneration; Renal Artery; Renin; Renin-Angiotensin System; Stem Cells; Water-Electrolyte Balance
PubMed: 33793334
DOI: 10.1161/CIRCRESAHA.121.318064 -
Pflugers Archiv : European Journal of... Aug 2022The protease renin, the key enzyme of the renin-angiotensin-aldosterone system, is mainly produced and secreted by juxtaglomerular cells in the kidney, which are located... (Review)
Review
The protease renin, the key enzyme of the renin-angiotensin-aldosterone system, is mainly produced and secreted by juxtaglomerular cells in the kidney, which are located in the walls of the afferent arterioles at their entrance into the glomeruli. When the body's demand for renin rises, the renin production capacity of the kidneys commonly increases by induction of renin expression in vascular smooth muscle cells and in extraglomerular mesangial cells. These cells undergo a reversible metaplastic cellular transformation in order to produce renin. Juxtaglomerular cells of the renin lineage have also been described to migrate into the glomerulus and differentiate into podocytes, epithelial cells or mesangial cells to restore damaged cells in states of glomerular disease. More recently, it could be shown that renin cells can also undergo an endocrine and metaplastic switch to erythropoietin-producing cells. This review aims to describe the high degree of plasticity of renin-producing cells of the kidneys and to analyze the underlying mechanisms.
Topics: Cell Differentiation; Juxtaglomerular Apparatus; Kidney; Kidney Glomerulus; Mesangial Cells; Myocytes, Smooth Muscle; Podocytes; Renin; Renin-Angiotensin System
PubMed: 35511367
DOI: 10.1007/s00424-022-02694-8 -
American Journal of Physiology.... May 2010Connexins (Cxs) are widely-expressed proteins that form gap junctions in most organs, including the kidney. In the renal vasculature, Cx37, Cx40, Cx43, and Cx45 are... (Review)
Review
Connexins (Cxs) are widely-expressed proteins that form gap junctions in most organs, including the kidney. In the renal vasculature, Cx37, Cx40, Cx43, and Cx45 are expressed, with predominant expression of Cx40 in the endothelial cells and Cx45 in the vascular smooth muscle cells. In the tubules, there is morphological evidence for the presence of gap junction plaques only in the proximal tubules. In the distal nephron, Cx30, Cx30.3, and Cx37 are expressed, but it is not known whether they form gap junctions connecting neighboring cells or whether they primarily act as hemichannels. As in other systems, the major function of Cxs in the kidney appears to be intercellular communication, although they may also form hemichannels that allow cellular secretion of large signaling molecules. Renal Cxs facilitate vascular conduction, juxtaglomerular apparatus calcium signaling, and tubular purinergic signaling. Accordingly, current evidence points to roles for these Cxs in several important regulatory mechanisms in the kidney, including the renin angiotensin system, tubuloglomerular feedback, and salt and water reabsorption. At the systemic level, renal Cxs may help regulate blood pressure and may be involved in hypertension and diabetes.
Topics: Animals; Connexins; Gap Junctions; Humans; Kidney; Renin-Angiotensin System; Water-Electrolyte Balance
PubMed: 20164205
DOI: 10.1152/ajpregu.00808.2009 -
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