Structure and function of different parts of nephron.pptx

Structure and function of different parts of nephron

1. Structure and function of different parts of nephron

2. Structure of Nephron The mammalian nephron is a long tube-like structure, varying from 35–55 mm long. The structure of the nephron comprises two significant portions: Renal Tubule Renal Corpuscle Renal Tubule The renal tubule is a long and convoluted structure that emerges from the glomerulus and can be divided into three parts based on function. The first part is called the proximal convoluted tubule (PCT) due to its proximity to the glomerulus; it stays in the renal cortex. The second part is called the loop of Henle , or the nephritic loop, because it forms a loop (with descending and ascending limbs) that goes through the renal medulla. The third part of the renal tubule is called the distal convoluted tubule (DCT), which is also restricted to the renal cortex. The capillaries of the glomerulus are enclosed by a cup-like structure called Bowman’s capsule. This structure extends to form highly coiled tubules called PCT. PCT continues to develop the loop of Henle, which ascends to DCT, which opens into the collecting duct. The primary function of tubules is reabsorption. In addition, tubular secretions help in urine formation without affecting the body's electrolyte balance.

3. Contd …. At one end, the tube is closed, folded, and expanded into a double-walled, cuplike facility called the Bowman’s capsule or renal corpuscular capsule,  which encloses a cluster of microscopic blood vessels called the glomerulus. This capsule and glomerulus together constitute the renal corpuscle. Renal Corpuscle The renal corpuscle consists of a glomerulus surrounded by a Bowman’s capsule. The glomerulus arises from an afferent arteriole and empties into an efferent arteriole. An efferent arteriole’s smaller diameter helps maintain high blood pressure in the glomerulus. The Bowman’s capsule is divided into three layers: Outer Parietal layer:  It comprises epithelial cells with minute pores of diameter 12nm. Middle Basement membrane:  This layer is selectively permeable. Inner Visceral Layer:  It consists of large nucleated cells called podocytes which bear finger-like projections called podocel .

4. Glomerulus The glomerulus is a loop of capillaries twisted into a ball shape , surrounded by the Bowman’s capsule. This is where blood ultrafiltration occurs, the first step in urine production . The filtration barrier consists of 3 components: Endothelial cells   of glomerular capillaries Glomerular basement membrane Epithelial cells of Bowman’s Capsule ( podocytes ) Structure Endothelial Cells The glomerular capillary endothelium has many perforations called  fenestrae,  which are pores about 70nm in diameter. These pores do not restrict the movement of water and proteins or large molecules but instead prevent the filtration of blood cells (e.g., RBCs). Surrounding the luminal surface of the endothelial cells is a  glycocalyx  consisting of  negatively charged glycosaminoglycans . This hinders the diffusion of negatively charged molecules by repelling them due to like charges.

5. Contd …. Glomerular Basement Membrane The basement membrane surrounds the capillary endothelium and is mostly made up of  type IV collagen ,  heparan sulfate proteoglycans  and  laminin . In particular, heparan sulfate proteoglycans help restrict the movement of negatively charged molecules across the basement membrane. The basement membrane consists of 3 layers: An inner thin layer  ( lamina rara interna ) A thick layer  ( lamina densa ) An outer dense layer  ( lamina rara externa ) These layers help to limit the filtration of intermediate and large-sized solutes. Epithelial Cells Podocytes  are specialised epithelial cells of Bowman’s capsule which form the visceral layer of the capsule. Foot-like processes project from these podocytes and interdigitate to form filtration slits. These filtration slits are bridged by a thin diaphragm (the  slit diaphragm ) with very small pores. The pores prevent large molecules, such as proteins, from crossing. Similar to the endothelial cell glycocalyx, negatively charged glycoproteins cover the podocytes, restricting the filtration of large anions.

6. Diagram showing the structure (a) and histology (b) of the glomerulus.

7. Ultrafiltration In the glomerulus, blood filters into the Bowman’s capsule through  ultrafiltration . Ultrafiltration is simply filtration that occurs under pressure. In this case, the  afferent   and   efferent arterioles  generate pressure. The afferent arteriole (at the proximal glomerulus)  dilates , while the efferent arteriole (at the distal glomerulus)  constricts . This creates a pressure gradient throughout the glomerulus, causing filtration under pressure. The  filtration rate of molecules  of the same charge across the filtration barrier is  inversely related  to their  molecular weight . Small molecules like glucose (180 Da) are freely filtered, whereas albumin (69 kDa ) can barely cross the barrier. The electrical charges on molecules also play a role in affecting their filtration rate. Negatively charged large molecules filter less easily than positively charged ones of the same size.

8. Structure of Proximal Convoluted Tubule The proximal convoluted tubule (PCT) has a high capacity for  reabsorption. Hence it has specialized features to aid with this. It is lined with simple cuboidal  epithelial cells , which have a brush border to increase the surface area on the apical side. The epithelial cells have large amounts of  mitochondria  to support the processes involved in transporting ions and substances. Moreover, they also have many channels on both the  apical  and  basolateral  membranes, providing a large surface area for the transport of ions and other substances. The proximal tubule can be divided into  pars convolute  and  pars recta. The pars convolute resides in the renal cortex and can further be divided into 2 segments; S1 (segment 1) and the proximal part of S2. The pars recta is a straight segment present in the outer medulla. It makes up the distal part of S2 and S3.

9. Histology of the nephron. The following structures are shown- 1 (Glomerulus), 2 (PCT) and 3 (DCT).

10. Function of PCT 1. Reabsorption A large amount of reabsorption occurs in the proximal convoluted tubule. Reabsorption is when water and solutes within the PCT are transported into the bloodstream. In the PCT this process occurs via bulk transport. The solutes and water move from the PCT to the interstitium and then into the peritubular  capillaries. The reabsorption in the proximal tubule is isosmotic. The proximal tubules reabsorb about 65% of water, sodium, potassium and chloride, 100% of glucose, 100% amino acids, and 85-90% of bicarbonate .   This reabsorption occurs due to the presence of channels on the basolateral (facing the interstitium ) and apical membranes (facing the tubular lumen). There are two routes through which reabsorption can take place:  paracellular  and  transcellular .  The transcellular route transports solutes  through a cell . The paracellular route transports solutes  between cells through the  intercellular space .

11. CONTD…. The driving force for the reabsorption in the PCT is sodium due to the presence of many sodium-linked symporters, e.g.,  sodium-glucose-linked transporters (SGLTs)  on the apical membrane. Sodium is usually  co-transported  with other solutes, e.g., amino acids and glucose, or in later tubule segments with chloride ions .   Thus sodium moving down its concentration allows other solutes to move against their concentration gradient. To create an electrochemical gradient for sodium, Na + -K + -ATPases on the basolateral surface pump out 3 Na +  ions in exchange for bringing 2 K +  ions into the cell. This transporter uses primary  active transport . This movement of Na +  creates an electrochemical gradient favoring the movement of Na +  into the cell from the tubule lumen. The S1 segment of the PCT is not permeable to urea and chloride ions. Hence their concentration increases in S1, which creates a concentration gradient that can be utilized in the S2 and S3 segments. Additional sodium is transported via an antiporter mechanism that reabsorbs sodium whilst secreting other ions, especially H + .

12. 2. Co-transport Co-transport refers to the movement of multiple solutes through the same channel. There are two types of co-transporters: Symporters  – transporters that move two (or more) molecules in the  same  direction e.g. SGLTs Antiporters  – transporters that move two (or more) molecules in  opposite  directions e.g. Na + /H +  antiporter The sodium concentration gradient allows other molecules, such as glucose, to be transported across the apical membrane against their concentration gradient. For example, SGLT transporters move glucose together with two sodium ions across the apical membrane. Glucose then crosses the basolateral membrane via facilitated diffusion. Na + /Amino acid   symporters  are present on the apical side of cells in the S1 segment of the PCT which reabsorbs all the amino acids in the PCT. Na + /H +  antiporter  is found on the apical surface of PCT cells. It is an  antiporter  and therefore transports ions across the cell membrane in opposite directions. In this case, the Na +  ions move into the tubular cells, while the H +  is expelled into the lumen. The primary function of this transporter is to maintain the pH.

13. 3. Movement of Water In the PCT, large volumes of solute are transported into the bloodstream. This means that as we move along the tubule, solute concentration in the tubule  decreases  while the solute concentration in the interstitium   increases . The difference in concentration gradient results in the water moving into the interstitium via  osmosis.   Water mainly takes the paracellular route to move out of the renal tubule but it can also take the transcellular route.

14. Diagram showing ion absorption and secretion within the proximal convoluted tubule.

15. 4. Secretion Secretion is when substances are removed from the blood and transported into the PCT. This is very useful as only 20% of the blood is  filtered  in the glomerulus every minute, so this provides an alternative route for substances to enter the tubular lumen. The PCT secretes: Organic acids and bases  – e.g. bile salts, oxalate and catecholamines (waste products of metabolism) Hydrogen ions (H + )  – important in maintaining acid/base balance in the body. H +  secretion allows reabsorption of bicarbonate via the use of the enzyme carbonic anhydrase. The net result is for every one molecule of H +  secreted, one molecule of bicarbonate and Na +  is reabsorbed into the blood stream. As the H +  is consumed in the reaction in the tubular lumen, there is no net excretion of H + . In this way, about 85% of filtered bicarbonate is reabsorbed in the PCT (the rest is reabsorbed by the intercalated cells at the DCT/CD later on). Drugs/toxins  – Secretion of organic cations such as dopamine or morphine occurs via the  H + /OC +  exchanger  on the apical side of the tubule cell, which is driven by the Na + /H +  antiporter. 

16. Loop of Henle Ion transport along the nephron is essential for the reabsorption of sodium and water, maintenance of plasma volume and blood pressure, and urine production. The Loop of Henle contributes to the absorption of approximately  25%  of filtered sodium and can be targeted by diuretic therapy. The Loop of Henle has a  hairpin configuration  with a thin descending limb and both a thin and thick ascending limb (TAL).  The thin descending and ascending segments have thin, squamous epithelial membranes with minimal metabolic activity. On the other hand, the TAL has cuboidal epithelial membranes and is relatively metabolically active. Function Thin Descending Limb The descending limb is highly permeable to water, with reabsorption occurring passively via aquaporin-1 (AQP1) channels. Very low amounts of urea, sodium (Na+), and other ions are also reabsorbed. As mentioned above, water reabsorption is driven by the counter-current multiplier system set up by the active reabsorption of sodium in the TAL.

17. Contd …. Thin Ascending Limb The thin ascending limb is  impermeable  to water due to it having no aquaporin channels. However, Na +  reabsorption still occurs passively through  epithelial Na +  ( eNaC ) channels . Chloride (Cl – ) ions are also reabsorbed in the thin ascending limb through  Cl –  channels . There is also some  paracellular  movement of Na +  and Cl –  due to the difference in osmolarity between the tubule and the interstitium . Thick Ascending Limb (TAL) The primary site of sodium reabsorption in the Loop of Henle is the thick ascending limb (TAL). The TAL is  impermeable  to water. Sodium reabsorption is active – the driver is the Na + /K +  ATPase on the basolateral membrane, which actively pumps  3 Na +  ions out of the cell  and  2 potassium (K + ) ions into the cell . By creating a low intracellular concentration of sodium, the inside of the cell becomes  negatively charged , creating an electrochemical gradient.

18. Contd …. The sodium moves into the cell (from the tubular lumen) down the electrical and chemical gradient through the  NKCC2   transporter  on the apical membrane. This transporter moves  one Na +  ion, one K +  ion, and two Cl –  ions  across the apical membrane. To prevent toxic build-up within the cell, potassium ions are transported back into the tubule by renal outer medullary potassium (ROMK) channels on the apical membrane.  Chloride ions are transported into the tissue fluid via CIC-KB channels. The overall effects of this process are: Removal of Na +  while retaining water in the tubules  leads to a hypotonic solution arriving at the DCT. Pumping Na +  into the interstitial space  contributes to a hyperosmotic environment in the kidney medulla. There is also some paracellular reabsorption of  magnesium ,  calcium , sodium, and potassium.

19. Counter-current multiplication As the thick ascending limb is impervious to water, the interstitium becomes concentrated with ions, increasing its osmolarity. This drives water reabsorption from the descending limb as water moves from low to high osmolarity areas. This system is known as  counter-current multiplication , allowing the kidneys to reabsorb around  99%  of filtered water. Please refer to the handwritten notes for further explanation.

20. Diagram showing ion and water reabsorption within the Loop of Henle.

21. Early Distal Convoluted Tubule The distal convoluted tubule can be subdivided into early and late sections, each with its functions. The role of early DCT is the absorption of ions, including sodium, chloride, and calcium. It is impermeable to water. The  macula densa  is situated in the first segment of the DCT – these are the sensing epithelium involved in  tubuloglomerular feedback.   This tubuloglomerular feedback controls glomerular filtration rate (GFR) and blood flow within the same nephron. The movement of these ions depends on the  Na + /K + -ATPase transporter  on the basolateral membrane of the cells. This excretes sodium ions into the extracellular fluid and brings potassium ions into the cell. This channel reduces intracellular sodium levels, creating a gradient favoring sodium movement into the cell via other channels on the apical membrane. This process is primary active transport , as ATP is directly needed to set up the gradient.

22. Contd …. The sodium concentration gradient generated allows sodium to enter the cell from the lumen of the distal convoluted tubule, which occurs through the  NCC  symporter (sodium-chloride cotransporter) alongside chloride ions. The chloride ions then exit the cell through a chloride ion uniporter on the basolateral membrane into the extracellular fluid, preventing accumulation within the cell.  Thiazide diuretics used to treat hypertension and heart failure inhibits the NCC. Calcium (Ca 2+ ) absorption also utilizes the sodium gradient established from the  Na + /K + -ATPase  channel. On the basolateral membrane, there is also an NCX channel (sodium-calcium antiporter). This is responsible for transporting calcium ions out into the extracellular fluid and sodium ions into the cell. The reduction in intracellular calcium creates a gradient that draws calcium ions from the lumen of the tubule into the cell through a calcium ion uniporter. Since ATP is not directly required, this is secondary active transport.  Parathyroid hormone (PTH)  also acts here – binding of PTH to its receptor causes more Ca 2+  channels to be inserted and increases Ca 2+  reabsorption.

23. Physiology of the Urinary System Every day, the kidneys filter gallons of fluid from the bloodstream. The normal physiology that takes place in the urinary system is as follows: Urine Formation- It is a result of three processes. Glomerular filtration- Water and solutes smaller than proteins are forced through the capillary walls and pores of the glomerular capsule into the renal tubule. Tubular reabsorption-  Water,  glucose , amino acids, and needed ions are transported out of the filtrate into the tubule cells and enter the capillary blood. Tubular secretion-  Hydrogen,  potassium ,  creatinine , and drugs are removed from the peritubular blood and secreted by the tubule cells into the filtrate.