MPP II 2.5 - RENAL PHYS. & PHARM I

• Lecture Title: Renal Physiology & Pharmacology I
• Date: 02-14-25

Renal Tubular Reabsorption and Secretion

• Summarizes the processes in different parts of the nephron like the proximal tubule, loop of Henle, distal tubule, and collecting duct
• Indicates hormonal regulation and whether substances are reabsorbed, secreted, or excreted
• Proximal tubule reabsorbs about 65% of solutes and water, including Na+, Cl-, HCO3−, K+, H2O, glucose, amino acids and secretes H+, organic acids and bases
• Thin descending limb of Henle's loop is permeable to H2O
• Early distal tubule reabsorbs include Na+, Cl-, Ca++, Mg++
• Medullary collecting duct reabsorbs Na+, Cl-, Urea, H2O when ADH is present, and secretes H+
• Thick ascending limb of Henle reabsorbs Na+, Cl-, K+, Ca++, HCO3, Mg++
• Late distal tubule and collecting tubule reabsorb Na+ and Cl- in principal cells when ADH is present, and secrete K+ and H+
• Type A intercalated cells secrete H+ and reabsorb HCO3-
• Reabsorption is supported by a network of peritubular capillaries which supply tubules with oxygen and nutrients
• The peritubular capillaries clear recovered fluid from interstitium, maintaining gradients for reabsorption
• Plasma colloid osmotic pressure (ΠPC) helps fluid reabsorption
• Capillary hydrostatic pressure (PPC) oppose reabsorption
• ΠPC is a form of osmotic exerted by proteins that pull fluid into the capillaries
• PPC declines over the length of the capillaries
• ΠPC and PPC are also known as Starling Forces

Reabsorption and Secretion in the Proximal Tubule (PT)

• Ultrafiltrate in the proximal tubule has a similar composition to plasma
• PT recovers >99% of water and major inorganic ions like Na+, K+, Mg2+, Ca2+, Cl-, HCO3-, H+ and phosphate
• PT also recovers sugars, amino acids, peptides, creatinine, and urea
• Most of the recovery of water and solutes occurs in the PT, paracellularly via osmosis through leaky walls
• PT PT plays a role in recovering larger solutes through reabsoprtion
• PT secrete organic compounds into the tubule lumen for urinary excretion

Tubular Reabsorption

• This involves the transfer of water and solutes from the tubule lumen to the interstitium and then to the peritubular capillary network via diffusion
• Two main pathways transport epithilia: paracellular absorption (diffusion) and transcellular reabsorption (active or passive diffusion)
• Transcellular reabsorption is powered by ATP, which is also consumed by Na+/K+ ATPase activity

Proximal Tubule Reabsorption Mechanisms

• Transepithelial transport is powered by ATP and nearly all energy goes to support Na+/K+ ATPase activity
• Step 1: Na+-K+ ATPase creates a Na+ gradient between outside and inside of cell
• Step 2: Ion transport creates a voltage gradient between tubule lumen and interstitium
• Step 3: Water follows Na+ by osmosis
• Step 4: Solutes are carried along in the water flow by solvent drag
• Step 5: Water reabsorption concentrates solutes remaining in the lumen

Sodium, Chloride, and Water Regulation

• Major electrolytes of the extracellular fluid
• Na+ and Cl- are the most abundantly filtered solutes
• Plasma Na+ concentration controls how water distributes between intracellular, interstitial, and plasma compartments
• Majority of Na+ recovered by PT
• Cl- follows Na+ because its driven inward by Na+'s positive charge
• Resorption of Na+ and Cl- creates an osmotic potential that drive water from lumen towards interstitium
• Na+ reabsorption is regulated by hormones in the kidney
• Net Na+ and Cl- movement sets up the interstitial gradient necessary for urine concentration
• Na+ and Cl- are reabsorbed in each segment
• Each of the transporters responsible is different in each segment

Principle Sites of Solute and Water Recovery and Secretion

• 98-99% of the water is reabsorbed in the PT

Proximal Convoluted Tubule: Sodium, Chloride, and Water Reabsorption

• PT cells recover organic solutes and HCO3- with Na+
• Transcellular Na+ reabsorption occurs with some paracellular leakage back towards the lumen
• The primary force in establishing the Na+ gradient is a form of ATPase
• Acid is synonymous with H+ (or NH3)

Proximal Convoluted Tubule: Glucose Reabsorption

• The vast majority of glucose is reabsorbed in the early PT and occurs transcellularly, mediated by “High-capacity, low affinity Na+-glucose cotransporter”
• SGLT2 recovers the bulk of glucose
• Proximal Straight Tubule reabsorbs whats left when theres very little glucose remaining through "High-affinity, low capacity 2Na+ -glucose cotransporter”
• SGLT1 reabsorbs and removes last of the glucose prior to the loop

Differences in Proximal and Distal Tubules

• Proximal tubule has a bulk action of fluid and water, and the distal tubules move against the steep gradients
• Proximal tubule is leaky while the distal tubule has high resistance
• The proximal tubule transport is controlled by gradients and the distal tubule is hormonally controlled

Therapeutic strategies in HF

• Chronic HF is typically managed by Fluid limitations, low dietary sodium intake, diuretics, inhibitors of the RAAS, and inhibitors of the sympathetic nervous system

Goals of pharmacologic intervention in Heart Failure

• Goals of treatment involve alleviating symptoms, slowing disease progression, and improving survival using Angiotensin-converting enzyme inhibitors, Angiotensin-receptor blockers, Aldosterone antagonists, Beta-blockers, Diuretics, Direct vaso- and venodilators and Inotropic agents

Diuretics Overview

• Drugs increase the volume of urine excreted by inhibiting renal ion transporters, which the decrease the reabsorption of Na+ at different nephron sites

Proximal Convoluted Tubule Pharmacological Targets: Carbonic Anhydrase Inhibitor

• Carbonic anhydrase inhibitors decreases reabsorption of HCO3- in the PCT
• Acetazolamide is a Carbonic Anhydrase Inhibitor that inhabits CA of both
• Decreases the exchange of Na+ in the results in a mild diuresis
• Since the other parts of the nephron can make up for the difference, this drug is not typically the first choice to treat this condition
• Decreases the production of aqueous humor lowering ocular pressure, treating glaucoma
• Prophylaxis help prevent weakness and shortness in breath for mountain sickness
• Can lead to metabolic acidosis, potassium depletion, and renal stone formation

Loop of Henle

• Renal function occurs in subsections of the Loop of Henle
• The function of the thin limbs in the kidney conveys fluid down through the medulla
• The limbs expose fluid to the corticopapillary osmotic gradient
• Fluid movement through the kidney is promoted by osmotic pressure gradients and are responsible for recovering water filtered from vasculature
• Distending Thin Limb (DTL): mostly impermeable to urea and Na, expresses aquaporins for water passage
• Ascending Thin Limb (ATL): is a transition site, turning the loop from water permeable to water impermeable and lacks aquaporins
• Thick Ascending Lim (TAL): Responsible for recovery of Na+, Cl-, K+, Ca2+, and Mg++
• Reabsorbs ~25% of Na+ and Cl-, 10% of K+ in Thick Ascending Limb
• Paracellular movement is driven by voltage difference

Thick Ascending Limb: Diuretics

• Unique in being impermeable to water
• Active reabsorption of Na+, K+, and Cl- mediated by a Na+/K+/2Cl- cotransporter
• Mg2+ and Ca2+ enter the interstitial fluid via the paracellular pathway due to the electrical gradient set up for the diuretic to be effective

Furosemide

• Is a common medication thats used as bumetanide and torsemide with highest efficacy in mobilizing fluid, and can treat pulmonary edema

Medication affects during loss/dysfunction of the ROMK channel

• dit ROMK's affecto on cotransporter which decreases solute conc in tubule to increase H20 in tubule, decreasing H20 for resurb while following solutes

Explore tubular reabsorption in kidneys: Na+/K+ ATPase pump role, solute transport in the proximal tubule, and influence of Starling forces. Understand how drugs affecting ATPase impact glucose reabsorption and the impact of Na+ variations.