Podocyte

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Podocyte
Renal corpuscle-en.svg
Renal corpuscle structure Blood flows in the afferent arteriole at the top, and out the efferent arteriole at the bottom. Blood flows through the capillaries of the glomerulus, where it is filtered by pressure. The podocytes (green) are wrapped around the capillaries. Blood is filtered through the slit diaphragm (or filtration slit), between the feet or processes of the podocytes. The filtered blood passes out the proximal tubule (yellow) on the right.
Details
Precursor Intermediate mesoderm
Location Bowman's capsule of the kidney
Identifiers
Latin podocytus
MeSH D050199
FMA 70967
Anatomical terms of microanatomy

Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. [1] Bowman's capsule filters the blood, retaining large molecules such as proteins while smaller molecules such as water, salts, and sugars are filtered as the first step in the formation of urine. Although various viscera have epithelial layers, the name visceral epithelial cells usually refers specifically to podocytes, which are specialized epithelial cells that reside in the visceral layer of the capsule.

Contents

The podocytes have long foot processes called pedicels, for which the cells are named ( podo- + -cyte ). The pedicels wrap around the capillaries and leave slits between them. Blood is filtered through these slits, each known as a filtration slit, slit diaphragm, or slit pore. [2] Several proteins are required for the pedicels to wrap around the capillaries and function. When infants are born with certain defects in these proteins, such as nephrin and CD2AP, their kidneys cannot function. People have variations in these proteins, and some variations may predispose them to kidney failure later in life. Nephrin is a zipper-like protein that forms the slit diaphragm, with spaces between the teeth of the zipper big enough to allow sugar and water through but too small to allow proteins through. Nephrin defects are responsible for congenital kidney failure. CD2AP regulates the podocyte cytoskeleton and stabilizes the slit diaphragm. [3] [4]

Structure

Diagram showing the basic physiologic mechanisms of the kidney Physiology of Nephron.png
Diagram showing the basic physiologic mechanisms of the kidney

Podocytes are found lining the Bowman's capsules in the nephrons of the kidney. The foot processes known as pedicels that extend from the podocytes wrap themselves around the capillaries of the glomerulus to form the filtration slits. The pedicels increase the surface area of the cells enabling efficient ultrafiltration. [5]

Pedicels of podocytes interdigitating to create numerous filtration slits around glomerular capillaries in 5000x electron micrograph Glomerulum of mouse kidney in Scanning Electron Microscope, magnification 5,000x.GIF
Pedicels of podocytes interdigitating to create numerous filtration slits around glomerular capillaries in 5000x electron micrograph

Podocytes secrete and maintain the basement membrane. [2]

There are numerous coated vesicles and coated pits along the basolateral domain of the podocytes which indicate a high rate of vesicular traffic.

Podocytes possess a well-developed endoplasmic reticulum and a large Golgi apparatus, indicative of a high capacity for protein synthesis and post-translational modifications.

There is also growing evidence of a large number of multivesicular bodies and other lysosomal components seen in these cells, indicating a high endocytic activity.

Function

Scheme of filtration barrier (blood-urine) in the kidney. A. The endothelial cells of the glomerulus; 1. pore (fenestra). B. Glomerular basement membrane: 1. lamina rara interna 2. lamina densa 3. lamina rara externa C. Podocytes: 1. enzymatic and structural protein 2. filtration slit 3. diaphragma Filtration barrier.svg
Scheme of filtration barrier (blood-urine) in the kidney.
A. The endothelial cells of the glomerulus; 1. pore (fenestra).
B. Glomerular basement membrane: 1. lamina rara interna 2. lamina densa 3. lamina rara externa
C. Podocytes: 1. enzymatic and structural protein 2. filtration slit 3. diaphragma

Podocytes have primary processes called trabeculae, which wrap around the glomerular capillaries. [6] The trabeculae in turn have secondary processes called pedicels. [6] Pedicels interdigitate, thereby giving rise to thin gaps called filtration slits. [2] The slits are covered by slit diaphragms which are composed of a number of cell-surface proteins including nephrin, podocalyxin, and P-cadherin, which restrict the passage of large macromolecules such as serum albumin and gamma globulin and ensure that they remain in the bloodstream. [7] Proteins that are required for the correct function of the slit diaphragm include nephrin, [8] NEPH1, NEPH2, [9] podocin, CD2AP. [10] and FAT1. [11]

The protein composition of podocytes and the slit diaphragm. Podo001.jpg
The protein composition of podocytes and the slit diaphragm.

Small molecules such as water, glucose, and ionic salts are able to pass through the filtration slits and form an ultrafiltrate in the tubular fluid, which is further processed by the nephron to produce urine.

Podocytes are also involved in regulation of glomerular filtration rate (GFR). When podocytes contract, they cause closure of filtration slits. This decreases the GFR by reducing the surface area available for filtration.

Clinical significance

Morphologic patterns of podocyte injury. Morphologic patterns of podocyte injury.jpg
Morphologic patterns of podocyte injury.

A loss of the foot processes of the podocytes (i.e., podocyte effacement) is a hallmark of minimal change disease, which has therefore sometimes been called foot process disease. [13]

Disruption of the filtration slits or destruction of the podocytes can lead to massive proteinuria, where large amounts of protein are lost from the blood.

An example of this occurs in the congenital disorder Finnish-type nephrosis, which is characterised by neonatal proteinuria leading to end-stage kidney failure. This disease has been found to be caused by a mutation in the nephrin gene.

In 2002 Professor Moin Saleem at the University of Bristol made the first conditionally immortalised human podocyte cell line. [14] [ further explanation needed ] This meant that podocytes could be grown and studied in the lab. Since then many discoveries have been made. Nephrotic syndrome occurs when there is a breakdown of the glomerular filtration barrier. The podocytes form one layer of the filtration barrier. Genetic mutations can cause podocyte dysfunction leading to an inability of the filtration barrier to restrict urinary protein loss. There are currently 53 genes known to play a role in genetic nephrotic syndrome. [15] In idiopathic nephrotic syndrome, there is no known genetic mutation. It is thought to be caused by a hitherto unknown circulating permeability factor. [16] Recent evidence suggests that the factor could be released by T-cells or B-cells, [17] [18] podocyte cell lines can be treated with plasma from patients with nephrotic syndrome to understand the specific responses of the podocyte to the circulating factor. There is growing evidence that the circulating factor could be signalling to the podocyte via the PAR-1 receptor. [19] [ further explanation needed ]

Presence of podocytes in urine has been proposed as an early diagnostic marker for preeclampsia. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Kidney</span> Organ that filters blood and produces urine

In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retroperitoneal space, and in adult humans are about 12 centimetres in length. They receive blood from the paired renal arteries; blood exits into the paired renal veins. Each kidney is attached to a ureter, a tube that carries excreted urine to the bladder.

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<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">Nephrotic syndrome</span> Collection of symptoms due to kidney damage

Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure.

<span class="mw-page-title-main">Bowman's capsule</span> Kidney structure which performs the first step in blood filtration

Bowman's capsule is a cup-like sac at the beginning of the tubular component of a nephron in the mammalian kidney that performs the first step in the filtration of blood to form urine. A glomerulus is enclosed in the sac. Fluids from blood in the glomerulus are collected in the Bowman's capsule.

<span class="mw-page-title-main">Renal corpuscle</span> Blood-filtering component of the nephron of the kidney

A renal corpuscle is the blood-filtering component of the nephron of the kidney. It consists of a glomerulus - a tuft of capillaries composed of endothelial cells, and a glomerular capsule known as Bowman's capsule.

<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.

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">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Minimal change disease</span> Medical condition

Minimal change disease is a disease affecting the kidneys which causes nephrotic syndrome. Nephrotic syndrome leads to the loss of significant amounts of protein in the urine, which causes the widespread edema and impaired kidney function commonly experienced by those affected by the disease. It is most common in children and has a peak incidence at 2 to 6 years of age. MCD is responsible for 10–25% of nephrotic syndrome cases in adults. It is also the most common cause of nephrotic syndrome of unclear cause (idiopathic) in children.

<span class="mw-page-title-main">Focal segmental glomerulosclerosis</span> Kidney disease

Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes. This process damages the filtration function of the kidney, resulting in protein presence in the urine due to protein loss. FSGS is a leading cause of excess protein loss—nephrotic syndrome—in children and adults. Signs and symptoms include proteinuria and edema. Kidney failure is a common long-term complication of the disease. FSGS can be classified as primary, secondary, or genetic, depending on whether a particular toxic or pathologic stressor or genetic predisposition can be identified as the cause. Diagnosis is established by renal biopsy, and treatment consists of glucocorticoids and other immune-modulatory drugs. Response to therapy is variable, with a significant portion of patients progressing to end-stage kidney failure. An American epidemiological study 20 years ago demonstrated that FSGS is estimated to occur in 7 persons per million, with males and African-Americans at higher risk.

Congenital nephrotic syndrome is a rare kidney disease which manifests in infants during the first 3 months of life, and is characterized by high levels of protein in the urine (proteinuria), low levels of protein in the blood, and swelling. This disease is primarily caused by genetic mutations which result in damage to components of the glomerular filtration barrier and allow for leakage of plasma proteins into the urinary space.

<span class="mw-page-title-main">Nephrin</span> Mammalian protein found in Homo sapiens

Nephrin is a protein necessary for the proper functioning of the renal filtration barrier. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane, and the podocytes of epithelial cells. Nephrin is a transmembrane protein that is a structural component of the slit diaphragm. They are present on the tips of the podocytes as an intricate mesh and convey strong negative charges which repel protein from crossing into the Bowman's space.

<span class="mw-page-title-main">Glomerular basement membrane</span>

The glomerular basement membrane of the kidney is the basal lamina layer of the glomerulus. The glomerular endothelial cells, the glomerular basement membrane, and the filtration slits between the podocytes perform the filtration function of the glomerulus, separating the blood in the capillaries from the filtrate that forms in Bowman's capsule. The glomerular basement membrane is a fusion of the endothelial cell and podocyte basal laminas, and is the main site of restriction of water flow. Glomerular basement membrane is secreted and maintained by podocyte cells.

Podocin is a protein component of the filtration slits of podocytes. Glomerular capillary endothelial cells, the glomerular basement membrane and the filtration slits function as the filtration barrier of the kidney glomerulus. Mutations in the podocin gene NPHS2 can cause nephrotic syndrome, such as focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Symptoms may develop in the first few months of life or later in childhood.

<span class="mw-page-title-main">NPHS2</span> Protein-coding gene in the species Homo sapiens

Podocin is a protein that in humans is encoded by the NPHS2 gene.

<span class="mw-page-title-main">CD2AP</span> Protein

CD2-associated protein is a protein that in humans is encoded by the CD2AP gene.

<span class="mw-page-title-main">KIRREL</span> Protein-coding gene in the species Homo sapiens

Kin of IRRE-like protein 1, also known as NEPH1, is a protein that in humans is encoded by the KIRREL gene.

Glomerulonephrosis is a non-inflammatory disease of the kidney (nephrosis) presenting primarily in the glomerulus as nephrotic syndrome. The nephron is the functional unit of the kidney and it contains the glomerulus, which acts as a filter for blood to retain proteins and blood lipids. Damage to these filtration units results in important blood contents being released as waste in urine. This disease can be characterized by symptoms such as fatigue, swelling, and foamy urine, and can lead to chronic kidney disease and ultimately end-stage renal disease, as well as cardiovascular diseases. Glomerulonephrosis can present as either primary glomerulonephrosis or secondary glomerulonephrosis.

Dendrin is a neural and renal protein whose exact function is still relatively unclear; however, its location in the brain and kidneys is well known as are some of the neural processes it affects. Within the brain, dendrin can be found in neurons and is most notably associated with sleep deprivation. Sleep deprivation causes some areas of the brain dendrin levels to increase, but this increase is insignificant and in total sleep deprivation causes a decrease of the mRNA and protein form of dendrin. Along with two other proteins, MAGI/S-SCAM and α-actinin, dendrin is linked to synaptic plasticity and memory formation in the brain. Nicotine levels have also been shown to have an effect on dendrin expression in the brain. Although unlike sleep deprivation, nicotine increases overall dendrin level. Originally thought to be a brain specific protein, there is now evidence to suggest that dendrin is also found in the kidneys. Dendrin is used to detect glomerulopathy or renal disease, based on its location in the kidneys. Within the kidneys it also works to prevent urinary protein loss. Most studies and information on dendrin pertain specifically to rat or mice brains.

References

  1. ↑ "Podocyte" "at Dorland's Medical Dictionary
  2. 1 2 3 Lote CJ (2012). "Glomerular Filtration". Principles of Renal Physiology (5th ed.). New York: Springer Science+Business Media. p. 34. doi:10.1007/978-1-4614-3785-7_3. ISBN   978-1-4614-3784-0.
  3. ↑ Wickelgren I (October 1999). "First components found for new kidney filter". Science. 286 (5438): 225–226. doi:10.1126/science.286.5438.225. PMID   10577188. S2CID   43237744.
  4. ↑ Löwik MM, Groenen PJ, Levtchenko EN, Monnens LA, van den Heuvel LP (November 2009). "Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis--a review". European Journal of Pediatrics. 168 (11): 1291–1304. doi:10.1007/s00431-009-1017-x. PMC   2745545 . PMID   19562370.
  5. ↑ Nosek TM. "Epithelium; Cell Types". Essentials of Human Physiology. Archived from the original on 24 March 2016.
  6. 1 2 Ovalle WK, Nahirney PC (28 February 2013). Netter's Essential Histology E-Book. Elsevier Health Sciences. ISBN   978-1-4557-0307-4 . Retrieved 2 June 2020.
  7. ↑ Jarad G, Miner JH (May 2009). "Update on the glomerular filtration barrier". Current Opinion in Nephrology and Hypertension. 18 (3): 226–232. doi:10.1097/mnh.0b013e3283296044. PMC   2895306 . PMID   19374010.
  8. ↑ Wartiovaara J, Ofverstedt LG, Khoshnoodi J, Zhang J, Mäkelä E, Sandin S, et al. (November 2004). "Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography". The Journal of Clinical Investigation. 114 (10): 1475–1483. doi:10.1172/JCI22562. PMC   525744 . PMID   15545998.
  9. ↑ Neumann-Haefelin E, Kramer-Zucker A, Slanchev K, Hartleben B, Noutsou F, Martin K, et al. (June 2010). "A model organism approach: defining the role of Neph proteins as regulators of neuron and kidney morphogenesis". Human Molecular Genetics. 19 (12): 2347–2359. doi:10.1093/hmg/ddq108. PMID   20233749.
  10. ↑ Fukasawa H, Bornheimer S, Kudlicka K, Farquhar MG (July 2009). "Slit diaphragms contain tight junction proteins". Journal of the American Society of Nephrology. 20 (7): 1491–1503. doi:10.1681/ASN.2008101117. PMC   2709684 . PMID   19478094.
  11. ↑ Ciani L, Patel A, Allen ND, ffrench-Constant C (May 2003). "Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype". Molecular and Cellular Biology. 23 (10): 3575–3582. doi:10.1128/mcb.23.10.3575-3582.2003. PMC   164754 . PMID   12724416.
  12. ↑ Cutrim ÉMM, Neves PDMM, Campos MAG, Wanderley DC, Teixeira-Júnior AAL, Muniz MPR; et al. (2022). "Collapsing Glomerulopathy: A Review by the Collapsing Brazilian Consortium". Front Med (Lausanne). 9: 846173. doi: 10.3389/fmed.2022.846173 . PMC   8927620 . PMID   35308512.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    - CC-BY 4.0 license
  13. ↑ Vivarelli M, Massella L, Ruggiero B, Emma F (February 2017). "Minimal Change Disease". Clinical Journal of the American Society of Nephrology. 12 (2): 332–345. doi:10.2215/CJN.05000516. PMC   5293332 . PMID   27940460.
  14. ↑ Saleem, Moin A.; O'Hare, Michael J.; Reiser, Jochen; Coward, Richard J.; Inward, Carol D.; Farren, Timothy; Xing, Chang Ying; Ni, Lan; Mathieson, Peter W.; Mundel, Peter (March 2002). "A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression". Journal of the American Society of Nephrology. 13 (3): 630–638. doi: 10.1681/ASN.V133630 . ISSN   1046-6673. PMID   11856766.
  15. ↑ Bierzynska, Agnieszka; McCarthy, Hugh J.; Soderquest, Katrina; Sen, Ethan S.; Colby, Elizabeth; Ding, Wen Y.; Nabhan, Marwa M.; Kerecuk, Larissa; Hegde, Shivram; Hughes, David; Marks, Stephen; Feather, Sally; Jones, Caroline; Webb, Nicholas J. A.; Ognjanovic, Milos (April 2017). "Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management". Kidney International. 91 (4): 937–947. doi:10.1016/j.kint.2016.10.013. hdl: 1983/c730c0d6-5527-435a-8c27-a99fd990a0e8 . ISSN   1523-1755. PMID   28117080. S2CID   4768411.
  16. ↑ Maas, Rutger J.; Deegens, Jeroen K.; Wetzels, Jack F. (2014). "Permeability factors in idiopathic nephrotic syndrome: historical perspectives and lessons for the future". Nephrology Dialysis Transplantation. academic.oup.com. 29 (12): 2207–2216. doi: 10.1093/ndt/gfu355 . Retrieved 26 April 2023.
  17. ↑ Hackl, Agnes; Zed, Seif El Din Abo; Diefenhardt, Paul; Binz-Lotter, Julia; Ehren, Rasmus; Weber, Lutz Thorsten (18 November 2021). "The role of the immune system in idiopathic nephrotic syndrome". Molecular and Cellular Pediatrics. 8 (1): 18. doi: 10.1186/s40348-021-00128-6 . ISSN   2194-7791. PMC   8600105 . PMID   34792685.
  18. ↑ May, Carl J.; Welsh, Gavin I.; Chesor, Musleeha; Lait, Phillipa J.; Schewitz-Bowers, Lauren P.; Lee, Richard W. J.; Saleem, Moin A. (1 October 2019). "Human Th17 cells produce a soluble mediator that increases podocyte motility via signaling pathways that mimic PAR-1 activation". American Journal of Physiology. Renal Physiology. 317 (4): F913–F921. doi:10.1152/ajprenal.00093.2019. ISSN   1522-1466. PMC   6843047 . PMID   31339775.
  19. ↑ May, Carl J.; Chesor, Musleeha; Hunter, Sarah E.; Hayes, Bryony; Barr, Rachel; Roberts, Tim; Barrington, Fern A.; Farmer, Louise; Ni, Lan; Jackson, Maisie; Snethen, Heidi; Tavakolidakhrabadi, Nadia; Goldstone, Max; Gilbert, Rodney; Beesley, Matt (March 2023). "Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events". Kidney International. 104 (2): 265–278. doi: 10.1016/j.kint.2023.02.031 . ISSN   0085-2538. PMID   36940798. S2CID   257639270.
  20. ↑ Konieczny A, Ryba M, Wartacz J, Czyżewska-Buczyńska A, Hruby Z, Witkiewicz W (2013). "Podocytes in urine, a novel biomarker of preeclampsia?" (PDF). Advances in Clinical and Experimental Medicine. 22 (2): 145–149. PMID   23709369.
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