Kidney Function: Lasix and DCT PDF

○ Lasix specifically blocks the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) on the apical membrane of the cells in the thick ascending limb. ○ By inhibiting NKCC2, Lasix prevents the reabsorption of sodium (Na⁺), potassium (K⁺), and chloride (Cl⁻) ions from the filtrate back in...

○ Lasix specifically blocks the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) on the apical membrane of the cells in the thick ascending limb. ○ By inhibiting NKCC2, Lasix prevents the reabsorption of sodium (Na⁺), potassium (K⁺), and chloride (Cl⁻) ions from the filtrate back into the blood. Impact on Osmotic Gradient: ○ The thick ascending limb is normally impermeable to water, so without NaCl reabsorption, the renal medullary interstitial fluid concentration decreases, disrupting the vertical osmotic gradient (VOG). ○ This reduction in the osmotic gradient decreases the kidney's ability to concentrate urine, leading to increased urine output. Increased Water Excretion (Diuretic Effect): ○ With less Na⁺ and Cl⁻ reabsorbed, more solute remains in the filtrate, increasing the osmolarity within the nephron. ○ Water remains in the filtrate due to osmotic balance, resulting in increased urine volume and diuresis (increased urine output). Therapeutic Uses Lasix is commonly prescribed to treat conditions such as: Edema (due to heart failure, liver disease, or kidney disease) Hypertension (high blood pressure) Hypercalcemia (high blood calcium levels, as Lasix increases calcium excretion by disrupting reabsorption) Summary  Lasix works by blocking the NKCC2 transporter in the thick ascending limb, inhibiting the reabsorption of Na⁺, K⁺, and Cl⁻. This action reduces the osmotic gradient in the medulla, increases urine output, and decreases the kidney’s ability to concentrate urine, which helps to relieve fluid overload and reduce blood pressure. DCT -Know the differences in the early and late distal tubules. -What two ions are secreted by the DCT? In the distal convoluted tubule (DCT), there are distinct differences between the early and late segments, both in terms of function and permeability. Additionally, the DCT is involved in the secretion of specific ions to help maintain electrolyte balance. Differences Between Early and Late Distal Tubules Early Distal Tubule: ○ Primary Function: Reabsorption of ions, particularly sodium (Na⁺) and chloride (Cl⁻). ○ Transport Mechanism: Na⁺ and Cl⁻ are reabsorbed via the Na⁺/Cl⁻ cotransporter on the apical membrane. ○ Permeability: The early DCT is impermeable to water under normal physiological conditions, which means that the filtrate becomes even more dilute as Na⁺ and Cl⁻ are reabsorbed without water following.  ○ Calcium Reabsorption: The early DCT is also a site for calcium (Ca²⁺) reabsorption, regulated by parathyroid hormone (PTH), which increases Ca²⁺ reabsorption when blood calcium levels are low. Late Distal Tubule: ○ Primary Function: Fine-tuning of Na⁺, K⁺, and water reabsorption and secretion, largely under hormonal regulation. ○ Hormonal Regulation: Aldosterone: Increases Na⁺ reabsorption and K⁺ secretion. Antidiuretic Hormone (ADH): Increases water reabsorption by inserting aquaporin channels in the cell membrane when the body needs to conserve water. ○ Permeability to Water: Unlike the early DCT, the late DCT’s permeability to water is regulated by ADH, which controls whether water is reabsorbed or excreted. Ions Secreted by the Distal Convoluted Tubule The DCT is involved in the secretion of two primary ions: Potassium (K⁺): ○ Secreted in the late DCT under the influence of aldosterone. Aldosterone increases the activity of Na⁺/K⁺ pumps and K⁺ channels, promoting K⁺ secretion into the tubular lumen. Hydrogen (H⁺):  ○ Secreted to help maintain acid-base balance. H⁺ ions are secreted into the tubular lumen, especially when the body needs to compensate for acidosis (excess acidity in the blood). Summary Early DCT: Primarily reabsorbs Na⁺ and Cl⁻ (impermeable to water) and is involved in Ca²⁺ reabsorption under PTH regulation. Late DCT: Regulates Na⁺, K⁺, and water reabsorption under hormonal control (aldosterone and ADH). Ions Secreted: The DCT secretes K⁺ and H⁺ ions to maintain electrolyte and acid-base balance. Early DCT In the early distal convoluted tubule (DCT), both sodium (Na⁺) and calcium (Ca²⁺) reabsorption play important roles in maintaining electrolyte balance, and they are regulated through specific transport mechanisms and hormones. Here’s an overview of how each process works: Na⁺ Reabsorption in the Early DCT Na⁺/Cl⁻ Co-transporter on the Apical Membrane: ○ Na⁺ reabsorption in the early DCT occurs via the Na⁺/Cl⁻ co-transporter located on the apical membrane (the side facing the tubular lumen). ○ This co-transporter simultaneously moves one Na⁺ ion and one Cl⁻ ion from the tubular fluid into the epithelial cell of the DCT.  ○ This is a form of secondary active transport because it relies on the Na⁺ gradient established by the Na⁺/K⁺ ATPase pump on the basolateral membrane (discussed below). Na⁺/K⁺ ATPase Pump on the Basolateral Membrane: ○ On the basolateral membrane (the side facing the interstitial fluid and blood), the Na⁺/K⁺ ATPase pump actively transports Na⁺ out of the cell and K⁺ into the cell, using ATP. ○ This pump maintains a low intracellular Na⁺ concentration, which drives the function of the Na⁺/Cl⁻ co-transporter on the apical membrane. Cl⁻ Channels on the Basolateral Membrane: ○ Once Cl⁻ enters the cell through the Na⁺/Cl⁻ co-transporter, it diffuses out of the cell into the interstitial fluid via Cl⁻ channels on the basolateral membrane. ○ The movement of Cl⁻ helps maintain charge balance and contributes to the electrochemical gradient across the cell. Ca²⁺ Reabsorption in the Early DCT Hormonal Regulation of Ca²⁺ Reabsorption: ○ Parathyroid Hormone (PTH) is the main hormone that regulates Ca²⁺ reabsorption in the early DCT. ○ When blood Ca²⁺ levels are low, PTH is released by the parathyroid glands. PTH then binds to receptors on cells in the early DCT, stimulating Ca²⁺ reabsorption. Calcium Channels on the Apical Membrane (TRPV5 Channels): ○ PTH increases the activity of TRPV5 Ca²⁺ channels on the apical membrane of DCT cells, allowing Ca²⁺ to move from the tubular lumen into the cell.  ○ This process is passive and driven by the concentration gradient of Ca²⁺. Calcium Transport Across the Basolateral Membrane: ○ Once inside the cell, Ca²⁺ is transported across the basolateral membrane into the interstitial fluid through: Na⁺/Ca²⁺ exchanger (NCX): Uses the Na⁺ gradient to move Ca²⁺ out of the cell while bringing Na⁺ in. Ca²⁺ ATPase pump: Actively transports Ca²⁺ out of the cell, which requires ATP. Additional Hormonal Influence: ○ Vitamin D can also enhance Ca²⁺ reabsorption by increasing the synthesis of proteins involved in Ca²⁺ transport. Summary Na⁺ Reabsorption: Occurs through the Na⁺/Cl⁻ co-transporter on the apical membrane, driven by the Na⁺ gradient from the Na⁺/K⁺ ATPase pump on the basolateral membrane. Ca²⁺ Reabsorption: Regulated by PTH, which increases the activity of Ca²⁺ channels (TRPV5) on the apical membrane, and Ca²⁺ is then transported out of the cell via the Na⁺/Ca²⁺ exchanger and Ca²⁺ ATPase on the basolateral membrane. Late DCT: What are principal cells? What do they do? What hormone do they respond to? Principal cells are specialized epithelial cells located in the late distal convoluted tubule (DCT) and the collecting ducts of the nephron. They play a crucial role in  maintaining the body’s water and electrolyte balance by regulating sodium (Na⁺), potassium (K⁺), and water reabsorption and secretion. Functions of Principal Cells Sodium (Na⁺) Reabsorption: ○ Principal cells reabsorb Na⁺ from the tubular fluid back into the blood. ○ This process is regulated by the hormone aldosterone, which increases the activity of Na⁺ channels on the apical membrane (the side facing the tubular lumen) and stimulates the Na⁺/K⁺ ATPase pump on the basolateral membrane. Potassium (K⁺) Secretion: ○ Principal cells also secrete K⁺ into the tubular fluid. ○ Aldosterone increases K⁺ secretion by stimulating the Na⁺/K⁺ ATPase pump (which pumps K⁺ into the cell) and by increasing the activity of K⁺ channels on the apical membrane, allowing K⁺ to move into the tubular lumen. Water Reabsorption: ○ Principal cells reabsorb water in response to the hormone antidiuretic hormone (ADH), also known as vasopressin. ○ When ADH is present, it triggers the insertion of aquaporin-2 (AQP2) channels into the apical membrane of principal cells, allowing water to be reabsorbed from the tubular fluid back into the bloodstream. ○ This process helps to concentrate the urine and conserve body water. Hormones Affecting Principal Cells Aldosterone:  ○ Released by the adrenal cortex in response to low blood sodium, low blood pressure, or high potassium levels. ○ Aldosterone increases Na⁺ reabsorption and K⁺ secretion by principal cells, thereby helping to regulate blood pressure and electrolyte balance. Antidiuretic Hormone (ADH): ○ Released by the posterior pituitary gland in response to high blood osmolarity or dehydration. ○ ADH makes principal cells more permeable to water by inserting AQP2 water channels into the apical membrane, allowing for water reabsorption and concentration of urine. Summary Principal cells are responsible for: Na⁺ reabsorption and K⁺ secretion under the influence of aldosterone. Water reabsorption under the influence of ADH. These cells help maintain blood pressure, blood volume, and electrolyte balance by adjusting Na⁺, K⁺, and water reabsorption and secretion in response to these hormones. know the relationship between macula densa cells and JG cells. What are they detected, what are each communicating with, who produces Renin? The macula densa cells and juxtaglomerular (JG) cells are part of the juxtaglomerular apparatus (JGA), which plays a crucial role in regulating blood pressure and the  glomerular filtration rate (GFR) through the renin-angiotensin-aldosterone system (RAAS). Relationship Between Macula Densa Cells and JG Cells Macula Densa Cells: ○ Located in the distal convoluted tubule (DCT), near the glomerulus. ○ These cells monitor the sodium chloride (NaCl) concentration in the filtrate. ○ When NaCl levels in the filtrate are low (indicating low blood pressure or low GFR), the macula densa cells signal the juxtaglomerular cells to release renin. ○ When NaCl levels are high, macula densa cells signal to reduce renin release to avoid excess blood pressure increase. Juxtaglomerular (JG) Cells: ○ Located in the walls of the afferent arteriole near the glomerulus. ○ JG cells are specialized smooth muscle cells that produce and secrete renin in response to signals from macula densa cells. ○ They can also respond directly to low blood pressure by detecting decreased stretch in the afferent arteriole, which also triggers renin release. Communication and Detection What They Detect: ○ Macula Densa Cells: Detect changes in NaCl concentration in the distal convoluted tubule, which reflects changes in GFR and blood pressure. ○ JG Cells: Detect changes in arterial blood pressure (by sensing stretch) and receive signals from the macula densa cells when NaCl levels are low. Communication:  ○ When NaCl levels are low, macula densa cells signal JG cells to release renin. This signaling is thought to involve local chemical messengers (such as prostaglandins) that communicate the need for renin release. ○ When NaCl levels are high, macula densa cells signal to reduce renin production, which helps decrease blood pressure and maintain balanced Na⁺ levels. Who Produces Renin? JG Cells produce and secrete renin in response to signals from macula densa cells or due to direct detection of low blood pressure. Summary Macula Densa Cells detect NaCl levels in the DCT and communicate with JG Cells to regulate renin release. JG Cells produce renin, which initiates the RAAS pathway, leading to vasoconstriction and aldosterone release to increase blood pressure and blood volume. Once produced, where does Renin go? What does it do? Once renin is produced by the juxtaglomerular (JG) cells in the kidneys, it is released into the bloodstream, where it plays a key role in the renin-angiotensin-aldosterone system (RAAS). Here’s a detailed breakdown of what happens next: Pathway and Action of Renin Renin Converts Angiotensinogen to Angiotensin I: ○ In the bloodstream, renin acts on a precursor protein called angiotensinogen, which is produced by the liver and circulates in the blood.  ○ Renin cleaves angiotensinogen, converting it into angiotensin I, an inactive form of the hormone. Conversion of Angiotensin I to Angiotensin II: ○ Angiotensin I travels through the bloodstream to the lungs, where it encounters angiotensin-converting enzyme (ACE), primarily found in lung endothelial cells. ○ ACE converts angiotensin I into angiotensin II, a powerful vasoconstrictor and active hormone in blood pressure regulation. Actions of Angiotensin II: ○ Vasoconstriction: Angiotensin II causes blood vessels to constrict, which increases systemic blood pressure. ○ Aldosterone Release: Angiotensin II stimulates the adrenal cortex to release aldosterone. Aldosterone acts on the distal tubule and collecting ducts of the nephron to increase sodium (Na⁺) reabsorption and potassium (K⁺) excretion. This Na⁺ reabsorption leads to water retention, which raises blood volume and blood pressure. ○ ADH Release: Angiotensin II also stimulates the release of antidiuretic hormone (ADH) from the posterior pituitary, which increases water reabsorption in the kidneys, further helping to increase blood volume and pressure. ○ Increased Thirst: Angiotensin II triggers thirst in the brain, prompting increased water intake, which also contributes to higher blood volume. Overall Effect