Tubuloglomerular feedback

Last updated

In the physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the renal tubules (a downstream area of the tubular fluid) is signaled to the glomerulus (an upstream area). Tubuloglomerular feedback is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of adenosine from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level. [1] [2] [3]

Contents

Background

The kidney maintains the electrolyte concentrations, osmolality, and acid-base balance of blood plasma within the narrow limits that are compatible with effective cellular function; and the kidney participates in blood pressure regulation and in the maintenance of steady whole-organism water volume [4]

Fluid flow through the nephron must be kept within a narrow range for normal renal function in order to not compromise the ability of the nephron to maintain salt and water balance. [5] Tubuloglomerular feedback (TGF) regulates tubular flow by detecting and correcting changes in GFR. Active transepithelial transport is used by the thick ascending limb of loop of Henle (TAL) cells to pump NaCl to the surrounding interstitium from luminal fluid. The tubular fluid is diluted because the cell's walls are water-impermeable and do not lose water as NaCl is actively reabsorbed. Thus, the TAL is an important segment of the TGF system, and its transport properties allow it to act as a key operator of the TGF system. [5] A reduction of GFR occurs as a result of TGF when NaCl concentration at the sensor site is increased within the physiological range of approximately 10 to 60 mM. [6]

The TGF mechanism is a negative feedback loop in which the chloride ion concentration is sensed downstream in the nephron by the macula densa (MD) cells in the tubular wall near the end of TAL and the glomerulus. The muscle tension in the afferent arteriole is modified based on the difference between the sensed concentration and a target concentration. [5] Vasodilation of the afferent arteriole, which results in increased glomerular filtration pressure and tubular fluid flow, occurs when MD cells detect a chloride concentration that is below a target value. A higher fluid flow rate in the TAL allows less time for dilution of the tubular fluid so that MD chloride concentration increases. [5] Glomerular flow is decreased if the chloride concentration is above the target value. Constricting the smooth muscle cells in the afferent arteriole, results in a reduced concentration of chloride at the MD. TGF stabilizes the fluid and solute delivery into the distal portion of the loop of Henle and maintain the rate of filtration near its ideal value using these mechanisms.

Mechanism

The macula densa is a collection of densely packed epithelial cells at the junction of the thick ascending limb (TAL) and distal convoluted tubule (DCT). As the TAL ascends through the renal cortex, it encounters its own glomerulus, bringing the macula densa to rest at the angle between the afferent and efferent arterioles. The macula densa's position enables it to rapidly alter afferent arteriolar resistance in response to changes in the flow rate through the distal nephron.

The macula densa uses the composition of the tubular fluid as an indicator of GFR. A large sodium chloride concentration is indicative of an elevated GFR, while low sodium chloride concentration indicates a depressed GFR. Sodium chloride is sensed by the macula densa mainly by an apical Na-K-2Cl cotransporter (NKCC2). The relationship between the TGF and NKCC2 can be seen through the administration of loop diuretics like furosemide. [7] Furosemide blocks NaCl reabsorption mediated by the NKCC2 at the ascending loop of henle, which leads to increased renin release. Excluding loop diuretic use, the usual situation that causes a reduction in reabsorption of NaCl via the NKCC2 at the macula densa (DCT) is a low tubular lumen concentration of NaCl due to low GFR. Reduced NaCl uptake via the NKCC2 at the macula densa leads to increased renin release, which leads to restoration of plasma volume, and to dilation of the afferent arterioles, which leads to increased renal plasma flow and increased GFR.

The macula densa's detection of elevated sodium chloride concentration in the tubular lumen, which leads to a decrease in GFR, is based on the concept of purinergic signaling. [1] [2] [8]

In response to increased flow of tubular fluid in the thick ascending limb/ increased sodium chloride (salt) concentration at the macula densa:

  1. Elevated filtration at the glomerulus or reduced reabsorption of sodium and water by the Proximal Convoluted Tubule causes the tubular fluid at the macula densa to have a higher concentration of sodium chloride.
  2. Apical Na-K-2Cl cotransporters (NKCC2), which are found on the surface of the macula densa cells, are exposed to the fluid with a higher sodium concentration, and as a result more sodium is transported into the cells.
  3. The macula densa cells do not have enough Na/K ATPases on their basolateral surface to excrete this added sodium. This results in an increase of the cell's osmolarity.
  4. Water flows into the cell along the osmotic gradient, causing the cell to swell. When the cell swells, ATP escapes through a basolateral, stretch-activated, non-selective Maxi-Anion channel. [9] The ATP is subsequently converted to adenosine by ecto-5′-nucleotidase. [10]
  5. Adenosine constricts the afferent arteriole by binding with high affinity to the A1 receptors [11] [12] a Gi/Go. Adenosine binds with much lower affinity to A2A and A2B [13] receptors causing dilation of efferent arterioles. [12]
  6. The binding of adenosine to the A1 receptor causes a complex signal cascade involving the Gi subunit deactivating Ac, thus reducing cAMP and the Go subunit activating PLC, IP3 and DAG. [14] The IP3 causes the release of intracellular calcium, which spreads to neighbouring cells via gap junctions creating a "TGF calcium wave". [10] This causes afferent arteriolar vasoconstriction, decreasing the glomerular filtrate rate.
  7. The Gi and increased intracellular calcium, cause a decrease in cAMP which inhibits Renin release from the juxtaglomerular cells. [14] In addition, when macula densa cells detect higher concentrations of Na and Cl, they inhibit nitric oxide synthetase (decreasing renin release), but the most important inhibitory mechanism of renin synthesis and release is elevations in juxtaglomerular cell calcium concentration. [7]

In response to decreased flow of tubular fluid in the thick ascending limb / decreased salt concentration at the macula densa:

  1. Reduced filtration at the glomerulus or increased reabsorption of sodium and water by the Proximal Convoluted Tubule causes fluid in the tubule at the macula densa to have a reduced concentration of sodium chloride.
  2. NKCC2 has a lower activity and subsequently causes a complicated signaling cascade involving the activation of: p38, (ERK½), (MAP) kinases, (COX-2) and microsomal prostaglandin E synthase (mPGES) in the macula densa. [7]
  3. This causes the synthesis and release of PGE2.
  4. PGE2 acts on EP2 and EP4 receptors in juxtaglomerular cells and causes renin release. [7]
  5. Renin release activates RAAS leading to many outcomes including an increased GFR.

The critical target of the trans-JGA signaling cascade is the glomerular afferent arteriole; its response consists of an increase in net vasoconstrictor tone resulting in reductions of glomerular capillary pressure (PGC) and glomerular plasma flow. Efferent arterioles appear to play a lesser role; experimental evidence supports both vasoconstriction and vasodilation, with perhaps the former in the lower range and the latter in the higher range of NaCl concentrations (2). When feedback regulation of afferent arteriolar tone is prevented by interrupting the feedback loop, and when the sensing mechanism is fully activated by saturating NaCl concentrations, TGF reduces GFR on average by approximately 45% and PGC by approximately 20%. Afferent arteriolar resistance increases by 50% or less, consistent with a radius reduction of approximately 10%, if Poiseuille's law holds. Thus, TGF-induced vasoconstriction is usually limited in magnitude. [6]

Modulation

A mediating agent is released or generated as a function of changes in luminal NaCl concentration. The size of the TGF response is directly dependent upon these changes. "In part because of the striking effect of deletion of A1 adenosine receptors (A1AR), adenosine generated from released ATP has been proposed as the critical TGF mediator. [6] A modulating agent affects the TGF response without input regarding luminal NaCl. The agents are vasoactive substances that alter either the magnitude or the sensitivity of the TGF response. [6]

Factors that decrease TGF sensitivity include: [15]

The threshold at which the loop of Henle flow rate initiates feedback responses is affected. A high protein diet affects the feedback activity by making the single nephron glomerular filtration rate higher, and the Na and Cl concentrations in early distal tubule fluid lower. The signal eliciting the TG feedback response is affected. The increased load on the kidney of high-protein diet is a result of an increase in reabsorption of NaCl. [17]

Factors that increase TGF sensitivity include: [15]

See also

Related Research Articles

Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds in the blood. It is largely related to insufficient or dysfunctional filtering of blood by the kidneys. It can lead to uremia and acute kidney injury if not controlled.

<span class="mw-page-title-main">Nephron</span> Microscopic structural and functional unit of the kidney

The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure called Bowman's capsule. The renal tubule extends from the capsule. The capsule and tubule are connected and are composed of epithelial cells with a lumen. A healthy adult has 1 to 1.5 million nephrons in each kidney. Blood is filtered as it passes through three layers: the endothelial cells of the capillary wall, its basement membrane, and between the foot processes of the podocytes of the lining of the capsule. The tubule has adjacent peritubular capillaries that run between the descending and ascending portions of the tubule. As the fluid from the capsule flows down into the tubule, it is processed by the epithelial cells lining the tubule: water is reabsorbed and substances are exchanged ; first with the interstitial fluid outside the tubules, and then into the plasma in the adjacent peritubular capillaries through the endothelial cells lining that capillary. This process regulates the volume of body fluid as well as levels of many body substances. At the end of the tubule, the remaining fluid—urine—exits: it is composed of water, metabolic waste, and toxins.

<span class="mw-page-title-main">Renin</span> Aspartic protease protein and enzyme

Renin, also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the renin–angiotensin–aldosterone axis—that increases the volume of extracellular fluid and causes arterial vasoconstriction. Thus, it increases the body's mean arterial blood pressure.

<span class="mw-page-title-main">Renin–angiotensin system</span> Hormone system

The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance.

<span class="mw-page-title-main">Angiotensin</span> Group of peptide hormones in mammals

Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.

<span class="mw-page-title-main">Juxtaglomerular apparatus</span> Structure that regulates function of each nephron

The juxtaglomerular apparatus is a structure in the kidney that regulates the function of each nephron, the functional units of the kidney. The juxtaglomerular apparatus is named because it is next to (juxta-) the glomerulus.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Assessment of kidney function</span> Ways of assessing the function of the kidneys

Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.

<span class="mw-page-title-main">Glomerulus (kidney)</span> Functional unit of nephron

The glomerulus is a network of small blood vessels (capillaries) known as a tuft, located at the beginning of a nephron in the kidney. Each of the two kidneys contains about one million nephrons. The tuft is structurally supported by the mesangium, composed of intraglomerular mesangial cells. The blood is filtered across the capillary walls of this tuft through the glomerular filtration barrier, which yields its filtrate of water and soluble substances to a cup-like sac known as Bowman's capsule. The filtrate then enters the renal tubule of the nephron.

<span class="mw-page-title-main">Macula densa</span> A region of juxtaglomerular apparatus in nephron of kidney

In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule where it touches the glomerulus. Specifically, the macula densa is found in the terminal portion of the distal straight tubule, after which the distal convoluted tubule begins.

Mesangial cells are specialised cells in the kidney that make up the mesangium of the glomerulus. Together with the mesangial matrix, they form the vascular pole of the renal corpuscle. The mesangial cell population accounts for approximately 30-40% of the total cells in the glomerulus. Mesangial cells can be categorized as either extraglomerular mesangial cells or intraglomerular mesangial cells, based on their relative location to the glomerulus. The extraglomerular mesangial cells are found between the afferent and efferent arterioles towards the vascular pole of the glomerulus. The extraglomerular mesangial cells are adjacent to the intraglomerular mesangial cells that are located inside the glomerulus and in between the capillaries. The primary function of mesangial cells is to remove trapped residues and aggregated protein from the basement membrane thus keeping the filter free of debris. The contractile properties of mesangial cells have been shown to be insignificant in changing the filtration pressure of the glomerulus.

<span class="mw-page-title-main">Loop diuretic</span> Diuretics that act along the loop of Henle in the kidneys

Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in nephrons of the kidneys. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

An osmoreceptor is a sensory receptor primarily found in the hypothalamus of most homeothermic organisms that detects changes in osmotic pressure. Osmoreceptors can be found in several structures, including two of the circumventricular organs – the vascular organ of the lamina terminalis, and the subfornical organ. They contribute to osmoregulation, controlling fluid balance in the body. Osmoreceptors are also found in the kidneys where they also modulate osmolality.

<span class="mw-page-title-main">Juxtaglomerular cell</span> Cell in kidneys that produces & secretes renin

Juxtaglomerular cells, also known as juxtaglomerular granular cells are cells in the kidney that synthesize, store, and secrete the enzyme renin. They are specialized smooth muscle cells mainly in the walls of the afferent arterioles that deliver blood to the glomerulus. In synthesizing renin, they play a critical role in the renin–angiotensin system and thus in autoregulation of the kidney.

<span class="mw-page-title-main">Afferent arterioles</span> Blood vessels supplying nephrons of kidneys

The afferent arterioles are a group of blood vessels that supply the nephrons in many excretory systems. They play an important role in the regulation of blood pressure as a part of the tubuloglomerular feedback mechanism.

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

<span class="mw-page-title-main">Ascending limb of loop of Henle</span>

Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin and thick ascending limb; the thick portion is also known as the distal straight tubule, in contrast with the distal convoluted tubule downstream.

<span class="mw-page-title-main">Ultrafiltration (kidney)</span> Filtration by a semi-permeable membrane

In renal physiology, ultrafiltration occurs at the barrier between the blood and the filtrate in the glomerular capsule in the kidneys. As in nonbiological examples of ultrafiltration, pressure and concentration gradients lead to a separation through a semipermeable membrane. The Bowman's capsule contains a dense capillary network called the glomerulus. Blood flows into these capillaries through the afferent arterioles and leaves through the efferent arterioles.

<span class="mw-page-title-main">Autoregulation</span>

Autoregulation is a process within many biological systems, resulting from an internal adaptive mechanism that works to adjust that system's response to stimuli. While most systems of the body show some degree of autoregulation, it is most clearly observed in the kidney, the heart, and the brain. Perfusion of these organs is essential for life, and through autoregulation the body can divert blood where it is most needed.

References

  1. 1 2 Arulkumaran N, Turner CM, Sixma ML, Singer M, Unwin R, Tam FW (1 January 2013). "Purinergic signaling in inflammatory renal disease". Frontiers in Physiology. 4: 194. doi: 10.3389/fphys.2013.00194 . PMC   3725473 . PMID   23908631. Extracellular adenosine contributes to the regulation of GFR. Renal interstitial adenosine is mainly derived from dephosphorylation of released ATP, AMP, or cAMP by the enzyme ecto-5′-nucleotidase (CD73) (Le Hir and Kaissling, 1993). This enzyme catalyzes the dephosphorylation of 5′-AMP or 5′-IMP to adenosine or inosine, respectively, and is located primarily on the external membranes and mitochondria of proximal tubule cells, but not in distal tubule or collecting duct cells (Miller et al., 1978). ATP consumed in active transport by the macula densa also contributes to the formation of adenosine by 5- nucleotidase (Thomson et al., 2000). Extracellular adenosine activates A1 receptors on vascular afferent arteriolar smooth muscle cells, resulting in vasoconstriction and a reduction in GFR (Schnermann et al., 1990).
  2. 1 2 Praetorius HA, Leipziger J (1 March 2010). "Intrarenal purinergic signaling in the control of renal tubular transport". Annual Review of Physiology. 72 (1): 377–93. doi:10.1146/annurev-physiol-021909-135825. PMID   20148681.
  3. ↑ Persson AE, Lai EY, Gao X, Carlström M, Patzak A (1 January 2013). "Interactions between adenosine, angiotensin II and nitric oxide on the afferent arteriole influence sensitivity of the tubuloglomerular feedback". Frontiers in Physiology. 4: 187. doi: 10.3389/fphys.2013.00187 . PMC   3714451 . PMID   23882224.
  4. ↑ Widmaier EP, Raff H, Strang KT (2016). Vander's Human Physiology: The Mechanisms of Body Function. New York, NY: McGraw-Hill Education.
  5. 1 2 3 4 Ryu H, Layton AT (March 2014). "Tubular fluid flow and distal NaCl delivery mediated by tubuloglomerular feedback in the rat kidney". Journal of Mathematical Biology. 68 (4): 1023–49. doi:10.1007/s00285-013-0667-5. PMC   3757103 . PMID   23529284.
  6. 1 2 3 4 Schnermann J (2015). "Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by tubuloglomerular feedback: a quantitative assessment". Annual Review of Physiology. 77: 301–22. doi: 10.1146/annurev-physiol-021014-071829 . PMID   25668021.
  7. 1 2 3 4 Peti-Peterdi J, Harris RC (July 2010). "Macula densa sensing and signaling mechanisms of renin release". Journal of the American Society of Nephrology. 21 (7): 1093–6. doi:10.1681/ASN.2009070759. PMC   4577295 . PMID   20360309.
  8. ↑ Carlström M, Wilcox CS, Welch WJ (August 2010). "Adenosine A(2) receptors modulate tubuloglomerular feedback". American Journal of Physiology. Renal Physiology. 299 (2): F412-7. doi:10.1152/ajprenal.00211.2010. PMC   2928527 . PMID   20519378.
  9. ↑ Komlosi P, Peti-Peterdi J, Fuson AL, Fintha A, Rosivall L, Bell PD (June 2004). "Macula densa basolateral ATP release is regulated by luminal [NaCl] and dietary salt intake". American Journal of Physiology. Renal Physiology. 286 (6): F1054-8. doi:10.1152/ajprenal.00336.2003. PMID   14749255. S2CID   15170688.
  10. 1 2 Burnstock G, Evans LC, Bailey MA (March 2014). "Purinergic signalling in the kidney in health and disease". Purinergic Signalling. 10 (1): 71–101. doi:10.1007/s11302-013-9400-5. PMC   3944043 . PMID   24265071.
  11. ↑ Spielman WS, Arend LJ (February 1991). "Adenosine receptors and signaling in the kidney". Hypertension. 17 (2): 117–30. doi: 10.1161/01.HYP.17.2.117 . PMID   1991645.
  12. 1 2 Vallon V, Osswald H (2009). "Adenosine receptors and the kidney". Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology. Vol. 193. pp. 443–70. doi:10.1007/978-3-540-89615-9_15. ISBN   978-3-540-89614-2. PMC   6027627 . PMID   19639291.
  13. ↑ Feng MG, Navar LG (August 2010). "Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation". American Journal of Physiology. Renal Physiology. 299 (2): F310-5. doi:10.1152/ajprenal.00149.2010. PMC   2928524 . PMID   20462966.
  14. 1 2 Ortiz-Capisano MC, Atchison DK, Harding P, Lasley RD, Beierwaltes WH (October 2013). "Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway". American Journal of Physiology. Renal Physiology. 305 (8): F1209-19. doi:10.1152/ajprenal.00710.2012. PMC   3798729 . PMID   23884142.
  15. 1 2 Boron WF, Boulpaep EL (2005). Medical Physiology: A Cellular And Molecular Approach. Philadelphia, Pa.: Elsevier Saunders. ISBN   978-1-4160-2328-9.
  16. ↑ Song J, Lu Y, Lai EY, Wei J, Wang L, Chandrashekar K, Wang S, Shen C, Juncos LA, Liu R (January 2015). "Oxidative status in the macula densa modulates tubuloglomerular feedback responsiveness in angiotensin II-induced hypertension". Acta Physiologica. 213 (1): 249–58. doi:10.1111/apha.12358. PMC   4389650 . PMID   25089004.
  17. ↑ Seney FD, Persson EG, Wright FS (January 1987). "Modification of tubuloglomerular feedback signal by dietary protein". The American Journal of Physiology. 252 (1 Pt 2): F83–90. doi:10.1152/ajprenal.1987.252.1.F83. PMID   3812704.
  18. ↑ Wang H, D'Ambrosio MA, Garvin JL, Ren Y, Carretero OA (October 2013). "Connecting tubule glomerular feedback in hypertension". Hypertension. 62 (4): 738–45. doi:10.1161/HYPERTENSIONAHA.113.01846. PMC   3867812 . PMID   23959547.
  19. ↑ Wang H, Romero CA, Masjoan Juncos JX, Monu SR, Peterson EL, Carretero OA (December 2017). "Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF)". American Journal of Physiology. Renal Physiology. 313 (6): F1209–F1215. doi:10.1152/ajprenal.00320.2017. PMC   5814642 . PMID   28835421.
  20. ↑ Monu SR, Ren Y, Masjoan Juncos JX, Kutskill K, Wang H, Kumar N, Peterson EL, Carretero OA (April 2017). "Connecting tubule glomerular feedback mediates tubuloglomerular feedback resetting post-unilateral nephrectomy". American Journal of Physiology. Renal Physiology. 315 (4): F806–F811. doi:10.1152/ajprenal.00619.2016. PMC   6230744 . PMID   28424211.
  21. ↑ Ren Y, Janic B, Kutskill K, Peterson EL, Carretero OA (December 2016). "Mechanisms of connecting tubule glomerular feedback enhancement by aldosterone". American Journal of Physiology. Renal Physiology. 311 (6): F1182–F1188. doi:10.1152/ajprenal.00076.2016. PMC   5210193 . PMID   27413197.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.