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Bulletin Du Cancer Mar 2012The kidneys are responsible for the urinary excretion of uremic toxins and the regulation of several body systems such as intra and extracellular volume status,... (Review)
Review
The kidneys are responsible for the urinary excretion of uremic toxins and the regulation of several body systems such as intra and extracellular volume status, acid-base status, calcium and phosphate metabolism or erythropoiesis. They adapt quantitative and qualitative composition of the urine to keep these systems in balance. The flow of plasma is filtered in the range of 120 mL/min, and depends on the systemic and renal hemodynamics which is subject to self-regulation. The original urine will then be modified in successive segments of the nephron. The proximal nephron is to lead the massive reabsorption of water and essential elements such as sodium, bicarbonates, amino-acids and glucose. The distal nephron includes the distal convoluted tubule, the connector tube and the collecting duct. Its role is to adapt the quality composition of urine to the needs of the body.
Topics: Acid-Base Equilibrium; Body Water; Calcium; Erythropoietin; Extracellular Fluid; Humans; Kidney; Kidney Glomerulus; Kidney Tubules; Phosphorus; Renal Circulation; Urine
PubMed: 22157516
DOI: 10.1684/bdc.2011.1482 -
Metabolism: Clinical and Experimental Jun 2022Diabetic kidney disease (DKD) is a devastating microvascular complication associated with diabetes mellitus. Recently, the major focus of glomerular lesions of DKD has... (Review)
Review
Diabetic kidney disease (DKD) is a devastating microvascular complication associated with diabetes mellitus. Recently, the major focus of glomerular lesions of DKD has partly shifted to diabetic tubulopathy because of renal insufficiency and prognosis of patients is closely related to tubular atrophy and interstitial fibrosis. Indeed, the proximal tubule enriching in mitochondria for its high energy demand and dependence on aerobic metabolism has given us pause to focus primarily on the mitochondria-centric view of early diabetic tubulopathy. Multiple studies suggest that diabetes condition directly damages renal tubules, resulting in mitochondria dysfunction, including decreased bioenergetics, overproduction of mitochondrial reactive oxygen species (mtROSs), defective mitophagy and dynamics disturbances, which in turn trigger a series of metabolic abnormalities. However, the precise mechanism underlying mitochondrial dysfunction of renal tubules is still in its infancy. Understanding tubulointerstitial's pathobiology would facilitate the search for new biomarkers of DKD. In this Review, we summarize the current literature and postulate that the potential effects of mitochondrial dysfunction may accelerate initiation of early-stage diabetic tubulopathy, as well as their potential therapeutic strategies.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Kidney Tubules; Kidney Tubules, Proximal; Male; Mitochondria; Reactive Oxygen Species
PubMed: 35358497
DOI: 10.1016/j.metabol.2022.155195 -
Kidney International Mar 2018Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and... (Review)
Review
Renal tubules are the major component of the kidney and are vulnerable to a variety of injuries including hypoxia, proteinuria, toxins, metabolic disorders, and senescence. It has long been believed that tubules are the victim of injury. In this review, we shift this concept to renal tubules as a driving force in the progression of kidney diseases. In response to injury, tubular epithelial cells undergo changes and function as inflammatory and fibrogenic cells, with the consequent production of various bioactive molecules that drive interstitial inflammation and fibrosis. Innate immune-sensing receptors on the tubular epithelium also aggravate immune responses. Necroinflammation, an autoamplification loop between tubular cell death and interstitial inflammation, leads to the exacerbation of renal injury. Furthermore, tubular cells also play an active role in progressive renal injury via emerging mechanisms associated with a partial epithelial-mesenchymal transition, cell-cycle arrest at both G1/S and G2/M check points, and metabolic disorder. Thus, a better understanding the mechanisms by which tubular injury drives inflammation and fibrosis is necessary for the development of therapeutics to halt the progression of chronic kidney disease.
Topics: Acute Kidney Injury; Animals; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Proliferation; Cytokines; Disease Progression; Energy Metabolism; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Immunity, Innate; Inflammation Mediators; Kidney Tubules; Renal Insufficiency, Chronic; Signal Transduction
PubMed: 29361307
DOI: 10.1016/j.kint.2017.09.033 -
Trends in Cell Biology Oct 2022More than 800 million people suffer from kidney disease. Genetic studies and follow-up animal models and cell biological experiments indicate the key role of proximal... (Review)
Review
More than 800 million people suffer from kidney disease. Genetic studies and follow-up animal models and cell biological experiments indicate the key role of proximal tubule metabolism. Kidneys have one of the highest mitochondrial densities. Mitochondrial biogenesis, mitochondrial fusion and fission, and mitochondrial recycling, such as mitophagy are critical for proper mitochondrial function. Mitochondrial dysfunction can lead to an energetic crisis, orchestrate different types of cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis), and influence cellular calcium levels and redox status. Collectively, mitochondrial defects in renal tubules contribute to epithelial atrophy, inflammation, or cell death, orchestrating kidney disease development.
Topics: Animals; Humans; Kidney Diseases; Kidney Tubules; Mitochondria; Mitochondrial Dynamics; Mitophagy
PubMed: 35473814
DOI: 10.1016/j.tcb.2022.03.012 -
Hypertension (Dallas, Tex. : 1979) Oct 2020Diuretic resistance implies a failure to increase fluid and sodium (Na) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of... (Review)
Review
Diuretic resistance implies a failure to increase fluid and sodium (Na) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.
Topics: Diuretics; Drug Resistance; Heart Failure; Humans; Kidney Tubules; Treatment Failure
PubMed: 32829662
DOI: 10.1161/HYPERTENSIONAHA.120.15205 -
Journal of the American Society of... Aug 2015The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules... (Review)
Review
The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI.
Topics: Acute Kidney Injury; Capillaries; Disease Progression; Humans; Hypoxia; Kidney Tubules; Nephrosclerosis; Renal Circulation; Renal Insufficiency, Chronic; Vasoconstriction
PubMed: 25810494
DOI: 10.1681/ASN.2015010006 -
Theranostics 2023Mammalian renal proximal tubules can partially regenerate after acute kidney injury (AKI). However, cells participating in the renal proximal tubule regeneration remain...
Mammalian renal proximal tubules can partially regenerate after acute kidney injury (AKI). However, cells participating in the renal proximal tubule regeneration remain to be elucidated. Wilms' tumor 1 (WT1) expresses in a subtype of glomeruli parietal epithelial cells (PECs) in adult kidneys, it remains unclear whether these WT1 PECs play a role in renal regeneration/repair after AKI. Ischemia-reperfusion injury (IRI) mouse model was used to investigate the expression pattern of WT1 in the kidney after severe AKI. Conditional deletion of WT1 gene mice were generated using Pax8 and WT1 mice to examine the function of WT1. Then, genetic cell lineage tracing and single-cell RNA sequencing were performed to illustrate that WT1 PECs develop into WT1 proximal tubular epithelial cells (PTECs). Furthermore, clonogenicity, direct differentiation analysis and transplantation were used to reveal the stem cell-like properties of these WT1 PECs. The expression of WT1 protein in PECs and PTECs was increased after severe AKI. Conditional deletion of WT1 gene in PTECs and PECs aggravated renal tubular injury after severe AKI. WT1 PECs develop into WT1 PTECs via the transient scattered tubular cell stage, and these WT1 PECs possess specific stem cell-like properties. We discovered a group of WT1 PECs that promote renal proximal tubule regeneration/repair after severe AKI, and the expression of WT1 in PECs and PTECs is essential for renal proximal tubule regeneration after severe kidney injury.
Topics: Mice; Animals; Kidney Tubules; Kidney; Kidney Tubules, Proximal; Acute Kidney Injury; Cell Differentiation; Epithelial Cells; Reperfusion Injury; Mammals; WT1 Proteins
PubMed: 36923529
DOI: 10.7150/thno.79326 -
American Journal of Physiology. Renal... Jun 2019Afferent arteriole (Af-Art) diameter regulates pressure and flow into the glomerulus, which are the main determinants of the glomerular filtration rate. Thus, Af-Art... (Review)
Review
Afferent arteriole (Af-Art) diameter regulates pressure and flow into the glomerulus, which are the main determinants of the glomerular filtration rate. Thus, Af-Art resistance is crucial for Na filtration. Af-Arts play a role as integrative centers, where systemic and local systems interact to determine the final degree of resistance. The tubule of a single nephron contacts an Af-Art of the same nephron at two locations: in the transition of the thick ascending limb to the distal tubule (macula densa) and again in the connecting tubule. These two sites are the anatomic basis of two intrinsic feedback mechanisms: tubule-glomerular feedback and connecting tubule-glomerular feedback. The cross communications between the tubules and Af-Arts integrate tubular Na and water processing with the hemodynamic conditions of the kidneys. Tubule-glomerular feedback provides negative feedback that tends to avoid salt loss, and connecting tubule-glomerular feedback provides positive feedback that favors salt excretion by modulating tubule-glomerular feedback (resetting it) and increasing glomerular filtration rate. These feedback mechanisms are also exposed to systemic modulators (hormones and the nervous system); however, they can work in isolated kidneys or nephrons. The exaggerated activation or absence of any of these mechanisms may lead to disequilibrium in salt and water homeostasis, especially in extreme conditions (e.g., high-salt diet/low-salt diet) and may be part of the pathogenesis of some diseases. In this review, we focus on molecular signaling, feedback interactions, and the physiological roles of these two feedback mechanisms.
Topics: Animals; Epithelial Sodium Channels; Feedback, Physiological; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Glomerulus; Kidney Tubules; Renal Circulation; Sodium; Water-Electrolyte Balance; Water-Electrolyte Imbalance
PubMed: 30838873
DOI: 10.1152/ajprenal.00381.2018 -
Kidney International Nov 2006Excess fatty acids accompanied by triglyceride accumulation in parenchymal cells of multiple tissues including skeletal and cardiac myocytes, hepatocytes, and pancreatic... (Review)
Review
Excess fatty acids accompanied by triglyceride accumulation in parenchymal cells of multiple tissues including skeletal and cardiac myocytes, hepatocytes, and pancreatic beta cells results in chronic cellular dysfunction and injury. The process, now termed lipotoxicity, can account for many manifestations of the 'metabolic syndrome'. Most data suggest that the triglycerides serve primarily a storage function with toxicity deriving mainly from long-chain nonesterified fatty acids (NEFA) and their products such as ceramides and diacylglycerols. In the kidney, filtered NEFA carried on albumin can aggravate the chronic tubule damage and inflammatory phenotype that develop during proteinuric states and lipid loading of both glomerular and tubular cells is a common response to renal injury that contributes to progression of nephropathy. NEFA-induced mitochondrial dysfunction is the primary mechanism for energetic failure of proximal tubules during hypoxia/reoxygenation and persistent increases of tubule cell NEFA and triglycerides occur during acute renal failure in vivo in association with downregulation of mitochondrial and peroxisomal enzymes of beta oxidation. In acute renal failure models, peroxisome proliferator-activated receptor alpha ligand treatment can ameliorate the NEFA and triglyceride accumulation and limits tissue injury likely via both direct tubule actions and anti-inflammatory effects. Both acute and chronic kidney disease are associated with systemic manifestations of the metabolic syndrome.
Topics: Animals; Fatty Acids; Humans; Kidney Tubules; Metabolic Syndrome; Renal Insufficiency
PubMed: 16955100
DOI: 10.1038/sj.ki.5001834 -
Kidney International Jun 1996Aquaporins (AQPs) are a newly recognized family of transmembrane proteins that function as molecular water channels. At least four aquaporins are expressed in the kidney... (Review)
Review
Aquaporins (AQPs) are a newly recognized family of transmembrane proteins that function as molecular water channels. At least four aquaporins are expressed in the kidney where they mediate rapid water transport across water-permeable epithelia and play critical roles in urinary concentrating and diluting processes. AQP1 is constitutively expressed at extremely high levels in the proximal tubule and descending limb of Henle's loop. AQP2, -3 and -4 are expressed predominantly in the collecting duct system. AQP2 is the predominant water channel in the apical plasma membrane and AQP3 and -4 are found in the basolateral plasma membrane. Short-term regulation of collecting duct water permeability by vasopressin is largely a consequence of regulated trafficking of AQP2-containing vesicles to and from the apical plasma membrane.
Topics: Aquaporin 1; Aquaporin 2; Aquaporin 3; Aquaporin 4; Aquaporin 6; Aquaporins; Ion Channels; Kidney Tubules; Water
PubMed: 8743483
DOI: 10.1038/ki.1996.253