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Nature Reviews. Nephrology Dec 2023The regulation and preservation of distinct intracellular and extracellular solute microenvironments is crucial for the maintenance of cellular homeostasis. In mammals,... (Review)
Review
The regulation and preservation of distinct intracellular and extracellular solute microenvironments is crucial for the maintenance of cellular homeostasis. In mammals, the kidneys control bodily salt and water homeostasis. Specifically, the urine-concentrating mechanism within the renal medulla causes fluctuations in extracellular osmolarity, which enables cells of the kidney to either conserve or eliminate water and electrolytes, depending on the balance between intake and loss. However, relatively little is known about the subcellular and molecular changes caused by such osmotic stresses. Advances have shown that many cells, including those of the kidney, rapidly (within seconds) and reversibly (within minutes) assemble membraneless, nano-to-microscale subcellular assemblies termed biomolecular condensates via the biophysical process of hyperosmotic phase separation (HOPS). Mechanistically, osmotic cell compression mediates changes in intracellular hydration, concentration and molecular crowding, rendering HOPS one of many related phase-separation phenomena. Osmotic stress causes numerous homo-multimeric proteins to condense, thereby affecting gene expression and cell survival. HOPS rapidly regulates specific cellular biochemical processes before appropriate protective or corrective action by broader stress response mechanisms can be initiated. Here, we broadly survey emerging evidence for, and the impact of, biomolecular condensates in nephrology, where initial concentration buffering by HOPS and its subsequent cellular escalation mechanisms are expected to have important implications for kidney physiology and disease.
Topics: Humans; Animals; Biomolecular Condensates; Kidney; Water; Mammals
PubMed: 37752323
DOI: 10.1038/s41581-023-00767-0 -
Hypertension Research : Official... Nov 2021Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system,... (Review)
Review
Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system, the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla in the brain stem play critical roles in the regulation of sympathetic outflow to peripheral organs. Information from the peripheral circulation, including serum concentrations of sodium and angiotensin II, is conveyed to the PVN via adjacent structures with a weak blood-brain barrier. In addition, signals from baroreceptors, chemoreceptors and cardiopulmonary receptors as well as afferent input via the renal nerves are all integrated at the level of the PVN. The brain renin-angiotensin system and the balance between nitric oxide and reactive oxygen species in these brain areas also determine the final sympathetic outflow. Additionally, brain inflammatory responses have been shown to modulate these processes. Renal denervation interrupts both the afferent inputs from the kidney to the PVN and the efferent outputs from the PVN to the kidney, resulting in the suppression of sympathetic outflow and eliciting beneficial effects on both hypertension and heart failure.
Topics: Animals; Blood Pressure; Denervation; Kidney; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System
PubMed: 34518650
DOI: 10.1038/s41440-021-00746-7 -
Seminars in Nephrology Mar 2020The kidney is a highly metabolic organ that requires substantial adenosine triphosphate for the active transport required to maintain water and solute reabsorption.... (Review)
Review
The kidney is a highly metabolic organ that requires substantial adenosine triphosphate for the active transport required to maintain water and solute reabsorption. Aberrations in energy availability and energy utilization can lead to cellular dysfunction and death. Mitochondria are essential for efficient energy production. The pathogenesis of acute kidney injury is complex and varies with different types of injury. However, multiple distinct acute kidney injury syndromes share a common dysregulation of energy metabolism. Pathways of energy metabolism and mitochondrial dysfunction are emerging as critical drivers of acute kidney injury and represent new potential targets for treatment. This review shows the basic metabolic pathways that all cells depend on for life; describes how the kidney optimizes those pathways to meet its anatomic, physiologic, and metabolic needs; summarizes the importance of metabolic and mitochondrial dysfunction in acute kidney injury; and analyzes the mitochondrial processes that become dysregulated in acute kidney injury including mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and changes in mitochondrial energy metabolism.
Topics: Acute Kidney Injury; Animals; Energy Metabolism; Humans; Kidney; Kidney Cortex; Kidney Medulla; Metabolic Networks and Pathways; Mitochondria; Mitochondrial Dynamics; Mitophagy; Nephrons; Organelle Biogenesis
PubMed: 32303274
DOI: 10.1016/j.semnephrol.2020.01.002 -
Archives of Pathology & Laboratory... Sep 2021Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between... (Review)
Review
CONTEXT.—
Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between nonneoplastic structures. Although high-grade cortical tumors can rarely exhibit the same growth pattern, the infiltrative morphology should elicit a differential diagnosis to be considered in each case. However, these diagnoses can be challenging to distinguish, especially on small renal biopsy samples.
OBJECTIVE.—
To provide an overview of the clinical, gross, and microscopic findings; genetic and molecular alterations; and immunohistochemical evaluation of medullary-based renal tumors and other tumor types with overlapping morphologies and growth patterns.
DATA SOURCES.—
Literature review and personal observations were used to compile the information in this review.
CONCLUSIONS.—
Collecting duct carcinoma is a prototypical medullary-based tumor, and although diagnostic criteria exist, it remains a diagnosis of exclusion, especially with ancillary techniques aiding the recognition of established as well as more recently described neoplasms. Other medullary-based malignancies included in the differential diagnosis include renal medullary carcinoma/renal cell carcinoma unclassified with medullary phenotype, fumarate hydratase-deficient renal cell carcinoma, and upper tract urothelial carcinoma. Moreover, other rare entities should be excluded, including metastatic carcinoma, lymphoma, and melanoma. In addition to potential prognostic differences, accurate diagnoses can have important surgical and clinical management implications.
Topics: Diagnosis, Differential; Humans; Kidney Medulla; Kidney Neoplasms
PubMed: 33406251
DOI: 10.5858/arpa.2020-0464-RA -
Comprehensive Physiology Dec 2021Cardiac surgery-associated acute kidney injury and brain injury remain common despite ongoing efforts to improve both the equipment and procedures deployed during...
Cardiac surgery-associated acute kidney injury and brain injury remain common despite ongoing efforts to improve both the equipment and procedures deployed during cardiopulmonary bypass (CPB). The pathophysiology of injury of the kidney and brain during CPB is not completely understood. Nevertheless, renal (particularly in the medulla) and cerebral hypoxia and inflammation likely play critical roles. Multiple practical factors, including depth and mode of anesthesia, hemodilution, pump flow, and arterial pressure can influence oxygenation of the brain and kidney during CPB. Critically, these factors may have differential effects on these two vital organs. Systemic inflammatory pathways are activated during CPB through activation of the complement system, coagulation pathways, leukocytes, and the release of inflammatory cytokines. Local inflammation in the brain and kidney may be aggravated by ischemia (and thus hypoxia) and reperfusion (and thus oxidative stress) and activation of resident and infiltrating inflammatory cells. Various strategies, including manipulating perfusion conditions and administration of pharmacotherapies, could potentially be deployed to avoid or attenuate hypoxia and inflammation during CPB. Regarding manipulating perfusion conditions, based on experimental and clinical data, increasing standard pump flow and arterial pressure during CPB appears to offer the best hope to avoid hypoxia and injury, at least in the kidney. Pharmacological approaches, including use of anti-inflammatory agents such as dexmedetomidine and erythropoietin, have shown promise in preclinical models but have not been adequately tested in human trials. However, evidence for beneficial effects of corticosteroids on renal and neurological outcomes is lacking. © 2021 American Physiological Society. Compr Physiol 11:1-36, 2021.
Topics: Cardiopulmonary Bypass; Humans; Hypoxia; Hypoxia, Brain; Inflammation; Kidney
PubMed: 34964119
DOI: 10.1002/cphy.c210019 -
FASEB Journal : Official Publication of... Nov 2020The (pro)renin receptor (PRR), a key regulator of intrarenal renin-angiotensin system (RAS), is predominantly presented in podocytes, proximal tubules, distal convoluted... (Review)
Review
The (pro)renin receptor (PRR), a key regulator of intrarenal renin-angiotensin system (RAS), is predominantly presented in podocytes, proximal tubules, distal convoluted tubules, and the apical membrane of collecting duct A-type intercalated cells, and plays a crucial role in hypertension, cardiovascular disease, kidney disease, and fluid homeostasis. In addition to its well-known renin-regulatory function, increasing evidence suggests PRR can also act in a variety of intracellular signaling cascades independently of RAS in the renal medulla, including Wnt/β-catenin signaling, cyclooxygenase-2 (COX-2)/prostaglandin E (PGE ) signaling, and the apelinergic system, and work as a component of the vacuolar H -ATPase. PRR and these pathways regulate the expression/activity of each other that controlling blood pressure and renal functions. In this review, we highlight recent findings regarding the antagonistic interaction between PRR and ELABELA/apelin, the mutually stimulatory relationship between PRR and COX-2/PGE or Wnt/β-catenin signaling in the renal medulla, and their involvement in the regulation of intrarenal RAS thereby control blood pressure, renal injury, and urine concentrating ability in health and patho-physiological conditions. We also highlight the latest progress in the involvement of PRR for the vacuolar H -ATPase activity.
Topics: Animals; Humans; Hypertension; Kidney Diseases; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Signal Transduction; Prorenin Receptor
PubMed: 32975331
DOI: 10.1096/fj.202001711R -
British Journal of Anaesthesia Jun 2022Perioperative hypotension is common and associated with poor outcomes, including acute kidney injury (AKI). The mechanistic link between perioperative hypotension and... (Review)
Review
Perioperative hypotension is common and associated with poor outcomes, including acute kidney injury (AKI). The mechanistic link between perioperative hypotension and AKI is at least partly a consequence of the susceptibility of the kidney, and particularly the renal medulla, to ischaemia and hypoxia. Several critical gaps in our knowledge lead to uncertainty about when and how to intervene to prevent AKI attributable to perioperative hypotension. First, although we know that the risk of AKI varies with both the severity and duration of hypotensive episodes, 'safe' levels of arterial pressure have not been identified. Second, there have been few adequately powered clinical trials of interventions to avoid perioperative hypotension. Thus, most evidence surrounding perioperative hypotension is observational rather than based on randomised clinical trials. This means that the link between perioperative hypotension and AKI may represent association (where both phenomena reflect illness severity) rather than causation. Third, there is little information regarding the relative risks and benefits of various clinically available therapies (e.g. vasoconstrictors, i.v. fluids, or both) to treat and prevent perioperative hypotension, particularly with regard to renal medullary perfusion and oxygenation. Fourth, there are currently no validated, clinically feasible methods for real-time clinical monitoring of renal perfusion or oxygenation. Thus, future developments in perioperative kidney-protective strategies must rely on the development of methods to better monitor renal perfusion and oxygenation in the perioperative period, and thereby guide timing, intensity, type, and duration of interventions.
Topics: Acute Kidney Injury; Arterial Pressure; Humans; Hypotension; Kidney; Postoperative Complications; Vasoconstrictor Agents
PubMed: 35465952
DOI: 10.1016/j.bja.2022.03.002 -
Nature Reviews. Nephrology Jun 2021Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall's plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular... (Review)
Review
Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall's plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular calcification, Randall's plaques consist of calcium phosphate crystals mixed with an organic matrix that is rich in proteins, such as inter-α-trypsin inhibitor, as well as lipids, and includes membrane-bound vesicles or exosomes, collagen fibres and other components of the extracellular matrix. Kidney tissue surrounding Randall's plaques is associated with the presence of classically activated, pro-inflammatory macrophages (also termed M1) and downregulation of alternatively activated, anti-inflammatory macrophages (also termed M2). In animal models, crystal deposition in the kidneys has been associated with the production of reactive oxygen species, inflammasome activation and increased expression of molecules implicated in the inflammatory cascade, including osteopontin, matrix Gla protein and fetuin A (also known as α2-HS-glycoprotein). Many of these molecules, including osteopontin and matrix Gla protein, are well known inhibitors of vascular calcification. We propose that conditions of urine supersaturation promote kidney damage by inducing the production of reactive oxygen species and oxidative stress, and that the ensuing inflammatory immune response promotes Randall's plaque initiation and calcium stone formation.
Topics: Animals; Calcium Oxalate; Calcium Phosphates; Humans; Immunity; Inflammation; Kidney Calculi; Kidney Medulla
PubMed: 33514941
DOI: 10.1038/s41581-020-00392-1