RED Kidney 3 Learning objectives PDF

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Summary

1. Review the transport processes in the movement of solutes andwater across membranesReabsorption - 1 -luminal membrane; 2 -cytosol; 3 -basolateral membrane; 4 -interstitial fluid; 5 -capillary wall (tubule  blood)Secretion – opposite direction (blood  tubule)To pass through membranes: via channe...

Description

1. Review the transport processes in the movement of solutes and water across membranes Reabsorption - 1-luminal membrane; 2-cytosol; 3-basolateral membrane; 4-interstitial fluid; 5capillary wall (tubule  blood) Secretion – opposite direction (blood  tubule) To pass through membranes: via channel or carrier/ transporter The transcellular route can either be due to diffusion or active transport. The paracellular route is by diffusion via the tight junctions Hydrophilic molecules pass through a channel or a carrier/transporter to get across the membrane. Diffusion – down a concentration or electrochemical gradient (passive) • • •

simple (channels) faciliated (carriers) simple diffusion of water = osmosis

Active – against a concentration or electrochemical gradient • •

Primary = coupled directly to an energy source (e.g. ATP) Secondary = coupled indirectly to an energy source

Transport maximum, Tm = when capacity of carrier is exceeded

Reabsorption/ secretion in the kidney Passive • • •

No energy Movement down electrochemical/osmotic gradient Cl-, H2O, urea

Active • • •

Energy Movement against electrochemical/osmotic gradient Na+, Ca2+, amino acids, glucose, PO43-

2. Describe the PCT handling of Na+, K+, H+, HCO3-, amino acids, glucose, H2O and urea by either active or passive reabsorption Proximal convoluted tubule (PCT) • • • •

PCT wall is composed of single layer of cuboidal cells which interlock and are connected by tight junctions PCT cells have large/moderate density of microvilli and mitochondria Microvilli present on apical edge of cell increase the surface area available for reabsorption Mitochondria supply energy for reabsorption of nutrients, electrolytes and other substances that should not be lost from the body

Reabsorption and secretion occurs in the PCT however the PCT is the primary site of reabsorption of all solutes and this is dependant on the action of the Na+/K+ATPase pump Get reabsorption of Na+, Cl-, K+, HCO3 , glucose, water, urea amino acids into the peritubular capillary ei into the blood from the proximal convoluted tubule lumen. Get secretion of organic acids and bases into the PCT lumen from the peritubular capillaries and this is an active process and includes drugs such as diuretics, penicillins and opioids. The sodium potassium ATPase pump is located on the basolateral membrane of the PCT tubular cell and this membrane is located towards the peritubular capillary and the apical membrane is facing the PCT lumen. The ATPase pump pumps out 3 Na+ and 2 K+ into the tubular cell. It pumps sodium AGAINST its concentration gradient and pumps the potassium into the cell AGAINST its concentration gradient. Therefore, this antiporter requires energy to do this and uses ATP and hydrolyses ATP for this to occur. This is an example of primary active transport as the transporter uses an energy source ATP. There is a potassium channel on the basolateral membrane of the tubular cell which allows recycling of potassium ions to allow the ATPase pump to keep working. There is a Na+/H+ antiporter located on the apical side of the tubular cell. The antiporter pumps Na+ DOWN its concentration gradient as there is a lower concentration of Na+ due the ATPase pump, this antiporter helps to reabsorb Na+ from the filtrate in the PCT lumen. H+ is being secreted into the PCT lumen OUT of the tubular cell AGAINST its concentration gradient. The energy of moving Na+ DOWN its concentration gradient provides the antiporter with the energy to secrete H+ into the filtrate. This is an example of secondary active transport as the transport of H+ is indirectly coupled to an energy source.

There is a Na+/Glucose symporter ( SGLT-2) ( also acts as a Na+ AA symporter) on the apical membrane of the tubular cell and this allows Na+ diffusion into the cell as there is a low concentration of Na+ in the tubular cell due to the ATPase pump. The movement of Na+ DOWN its concentration gradient allows the movement on Glucose into the tubular cell AGAINST its concentration gradient as the movement of Na+ DOWN its concentration gradient provides the symporter with energy to pump glucose into the tubular cell as well. This is another example of secondary active transport. On the basolateral memebrane glucose is transported out of the tubular cell and into the peritubular capillaries. The SGLT-2 is a target for T2DM drugs as inhibition stops glucose reabsorption and therefore stays in the filtrate and is excreted via the urine. In the PCT tubular lumen the secreted H+ ions combine with bicarbonate ions to form carbonic acid. Then the carbonic acid is then broken down by an apical carbonic anhydrase enzyme back into H20 and CO2. The dissolved CO2 then diffuses into the tubular cell across the apical membrane and then forms carbonic acid inside the tubular cell as it combines with water via a carbonic anhydrase enzyme inside the tubular cell. However the carbonic acid can then split into H+ and HCO3- and then this is part of the cycle as the H+ is then secreted out of the cell by the Na+/H+ antiporter. This cycle leads to the net reabsorption of bicarbonate ions as they are also pumped out of the cell into the blood on the basolateral membrane and the apical membrane is not permeable to HCO3-, therefore the diffusion of CO2 allows for the Bicarbonate ion concentration to be restored.

osmosis is primarily through ‘leaky’ tight junctions and also via water channels known as aquaporins which provide high water permeability + This, together with osmotic gradient established by Na reabsorption, facilitates water reabsorption into the peritubular capillaries from the PCT tubular lumen

Ca2+, Cl- and K+ (some Na+) are reabsorbed (paracellular transport), as a result of active reabsorption of Na+ at basolateral membrane

Urea ~ 50% of urea is reabsorbed in the PCT • • •

Indirectly linked to Na+ reabsorption Reabsorption of H2O (secondary to Na+ reabsorption) creates a concentration gradient that favours passive reabsorption of urea Water moves away from the filtrate leaving the urea more concentration and therefore urea will move down its concentration gradient across the apical membrane into the peritubular capillaries

3. Describe the early DCT handling of Na+, Cl-, K+. Note the impermeable nature of the early DCT to water and urea • Early DCT reabsorbs Na+, K+ and Cl- but is virtually impermeable to H2O and urea The sodium potassium ATPase pump is located on the basolateral membrane of the PCT tubular cell and this membrane is located towards the peritubular capillary and the apical membrane is facing the early DCT lumen. The ATPase pump pumps out 3 Na+ and 2 K+ into the tubular cell. It pumps sodium AGAINST its concentration gradient and pumps the potassium into the cell AGAINST its concentration gradient. Therefore, this antiporter requires energy to do this and uses ATP and hydrolyses ATP for this to occur. This is an example of primary active transport as the transporter uses an energy source ATP. There is a potassium channel on the basolateral membrane of the tubular cell which allows recycling of potassium ions to allow the ATPase pump to keep working. The ATPase pumps out Na+ therefore Na+ diffuses into the early DCT tubular cell by the Na+/Cl- symporter. This symporter is located on the apical membreane. There is a chloride channel present on the basolateral membrane and this moves chloride ions by diffusion and helps to keep the Na+/Cl- symporter working. This symporter is the target for thiazide diuretics, the T Diuretics must be secreted into the PCT by an OAT.

4. Describe the late DCT and collecting duct handling of Na+, K+, Cl-, H+, HCO3 and H2O. Note that transport of K+, and H+ and HCO3is dependent on the cell type • Late DCT and CD are composed of principal (P) & intercalated (I) cells • • •

+ + Reabsorption of Na , secretion of K Site of action of aldosterone Site of action of antidiuretic hormone (ADH)

The P cells of the late DCT- P cells – reabsorb Na+, secrete K+ The sodium potassium ATPase pump is located on the basolateral membrane of the late DCT tubular cell and this membrane is located towards the peritubular capillary and the apical membrane is facing the DCT lumen. The ATPase pump pumps out 3 Na+ and 2 K+ into the tubular cell. It pumps sodium AGAINST its concentration gradient and pumps the potassium into the cell AGAINST its concentration gradient. Therefore, this antiporter requires energy to do this and uses ATP and hydrolyses ATP for this to occur. This is an example of primary active transport as the transporter uses an energy source ATP. There is a potassium channels on the basolateral membrane and apical membrane of the tubular cell

which allows recycling of potassium ions to allow the ATPase pump to keep working. Get overall secretion of K+ into the filtrate ( tubular lumen) The movement of Na+ out of the tubular P cell, allows the diffusion of Na+ to take place through Na+ selective channels ( ENaC) on the apical membrane. There is also a chloride channel on the basolateral membrane which allows the reabsorption of Cl- into the peritubular capillaries.

-

The I cells of the late DCT- I cells – reabsorb K+ and HCO3, secrete H

+

There isn’t an Na+/K+ ATPase but there is an H+ ATPase on the apical membrane causing secretion of H+ ions into the filtrate using ATP, it is a uniporter. Another transporter also sceretes H+ ions into the tubular lumen, the K+/H+ ATPase on the apical membrane and pumps K+ into the tubular I cell. The secreted H+ ions are involved in the reabsorption of bicarbonate ions as this is based on the activity of the enzyme carbonic anhydrase, this also allows for the cycling of H+ ions. Bicarbonate ions once formed from the breakdown of carbonic acid are transported across the basolateral membrane to be reabsorbed into the peritubular capillaries. The I cells are important in Acid-Base balance. Aldosterone also acts on I cells to stimulate secretion of H+ ions into the filtrate to be excreted in the urine.

5. Describe the activity of the hormones aldosterone and antidiuretic hormone (also known as vasopressin) on solute and water transport in the late DCT and collecting duct Aldosterone is a steroid hormone (mineralocorticoid) secreted by the adrenal cortex. Part of the RAAs and causes upregulation of expression of epithelial Na+ channels (ENaCs) and Na+/K+ATPase transporters (in P cells). Aldosterone is lipophilic and is able to diffuse across cell membranes and bind to an intracellular receptor known as the mineralocorticoid receptor, once bound it forms a complex and acts as a transcription factor to regulate gene expression by binding to promotor regions of the DNA in the nucleus to increase expression of the na+ selective channels and the Na+ /K+ ATPase pump. This leads to increased Na+ (and water) reabsorption, with accompanying K+ excretion. Also, aldosterone increases H+ secretion in the I cells. Vasopressin, AVP or antidiuretic hormone, ADH. ADH is synthesized in cells located in the hypothalamus and transported and stored in nerve terminals located in the posterior pituitary . ADH release stimulated by, increases in body fluid osmolality, fall in blood volume / pressure. Also stimulated by angiotensin II, nausea, acute stress. ADH acts on blood vessels to promote vasoconstriction, via V receptors (at higher concs of [ADH]) and acts on the Kidney (late DCT & CD) to 1 increase permeability and hence re-absorption of water Via V -receptors. ADH also promotes the 2 insertion of aquaporin 2 water channels in the apical membrane, increasing water permeability of

the late DCT and CD. ADH also causes increases permeability to urea as it causes phosphorylation of the UT-A urea receptors in the collecting duct, CD. This helps to maintain osmolality between the interstitial fluid and the tubular lumen which was caused by the increased water reabsorption....