Physiology of the Kidney PDF

# Physiology of the Kidney ## Basic Physiological Functions of the Kidney: - Filtration - Reabsorption - Secretion - Excretion ## Important Parameters of Renal Function: - Clearance - Extraction - RPF - RBF - GFR ## Transport Processes in the Proximal Tubule ## Transport at the Distal Connective...

# Physiology of the Kidney ## Basic Physiological Functions of the Kidney: - Filtration - Reabsorption - Secretion - Excretion ## Important Parameters of Renal Function: - Clearance - Extraction - RPF - RBF - GFR ## Transport Processes in the Proximal Tubule ## Transport at the Distal Connective Tubule and at the Collecting tubule; Water Transport ## Osmotic Gradient and Osmotic Capacity of the Kidney ## Transport in the Henle-Loop and the Distal Convoluted Tubule; Transport of Ammonia and Potassium ## Neural and Autoregulation of Renal Circulation ## Osmoregulation, Antidiuretic Hormone ## Volume Regulation in the Kidney; Renin-Angiotensin System, Aldosterone and ANP ## The Urinary Tract and the Process of Urination ## Nephron - functional unit - each kidney has 1 million nephrons - consists of: - Malpighi body - bowman's capsule - glomerulus - Tubular system - Proximal tubule - proximal convoluted tubule (PCT) - proximal straight tubule (PST) - Henle loop - Descending thin limb (DTL) - Ascending thin limb (ATL) - Ascending thick limb (TAL) - Distal tubule - distal convoluted tubule (DCT) - distal connective tubule (CNT) - Collecting duct - cortical collecting duct (CCD) - medullary collecting duct (MCD) The longer the Henle loop, the longer the time of liquid preservation (camels). Bird & reptilian-type nephrons lack Henle loop. ## Basic Physiological Functions of the Kidney ### Filtration: - EFP = GP-(CP+GCP) - EFP: Effective filtration pressure - GP: Glomerulus (hydrostatic) pressure - CP: Bowman's capsule pressure - GCP: Colloid-osmotic pressure of plasma - Filtration fraction= GFR/RPF = ±17 = 30% ### Tubular Reabsorption: - Reabsorption maximum: filtration is free but no excretion in urine due to intensive reabsorption. - Transfer maximum (Tm): upper limit of reabsorption/secretion - Ex. Tm (glucose) = 350 mg/min. If filtered load > 350 → body can't reabsorb & retain so much glucose → glucosuria (excretion in urine) ### Tubular Secretion: - Transfer of substance from peritubular capillaries to urinary tract - Secretion products perform other functions for the body - Secretion is done mostly by active transport ### Excretion: - Sum of filtration & secretion - Products of excretion are waste ### Linear Range: - Filtration increases linearly with increasing plasma concentration. ### SDL (Self Depression Limit): - Secretion decreases because the number of active cells available decreases. ### Saturation Range: - At certain plasma concentration, secretion becomes constant. ## Primary Functions ### Regulatory Functions: - Maintain isovolemia, isoionia & isosomosis of the organism - Regulation of the acid/base equilibrium (isohydria) with elimination of H ions - Cardiovascular regulation (through Angiotensin II synthesis) - Conservation of essential substances (water, electrolytes, glucose, amino acids) ### Excretory Functions: - excretion of natural by-products (urea, uric acid) - excretion of medicinal breakdown products - chemical neutralization & excretion of toxic materials ### Endocrine Function: - Angiotensin || production - Blood formation (erythropoietin hormone production) - Bone metabolism (calcitriol-hormone production) - Heat production (thyroid gland hormone production) - prostaglandin production ## Filtration - Functions above are facilitated by the kidney's high blood perfusion - 25% of cardiac output flows through the kidney. - Filtered amount per day - 180 L/day (or 120-125 ml/min - 99% absorbed back via tubules) - Proteins & RBC aren't filtered - Clinical - BP problems can indicate a kidney issue ## Filtration Barrier - The filtration barrier moves plasma inwards: - Fenestrated endothelium - Glomerular basement membrane (GBM) - Podocyte foot processes with interconnecting slit diaphragms - The filtration barrier is size-selective and restricts plasma molecules based on size, shape & charge (i.e. proteins - negative) - GBM has also a charge filter - negatively charged molecules have less access than positive (i.e proteins - negative) - Structural networks of type IV collagen & laminin linked through nidogen - Negatively charged proteoglycans - serve as anionic filtration barrier - Podocytes - ultimate barrier for proteins size of albumin - Nephrin - podocyte-podocyte interaction ## Double Capillarization: - Glomerular part & peritubular capillary (Characteristic of mammals) - Enabling regulation of water - Osmolality grows higher within the medulla. The higher the osmolality, the higher the ability to preserve water. - Peritubular capillaries are key to osmolality capabilities - counter current & concentrate urine within medullary interstitium (so it doesn't wash out) ## Important Parameters of Renal Function ### Clearance: - Volume of plasma completely cleared of a substance by kidney filtration per time unit: - High clearance - substance can be cleared in one pass through kidney - Low clearance – substrate may not be cleared at all by kidneys - U: Substance concentration in urine - P: Substance concentration in plasma - V: Produced urine per minute - Importance: Some functional disorders can be quantitatively characterized by clearance. #### Certain Substances are Exclusively Filtered - Certain substances are exclusively filtered (neither reabsorbed or secreted and eventually excreted – i.e inulin) - Their clearance is equal to the rate of glomerular filtration rate (GFR) - If C(x) > C(in) = secretion (substance is also secreted from peritubular vessels, not just from glomerulus) - If C(x) < C(in) = reabsorption (substance is also reabsorbed from peritubular vessels, not urea) - C(glucose) = 0 = complete reabsorption #### Inulin Concentration - Inulin concentration in plasma doesn’t influence its clearance (it is only filtered) #### Other Substances: - Other substances are filtered & secreted entirely (i.e PAH) - Their clearance is equal to the renal plasma flow (RPF) - PAH clearance is constant at low plasma concentration (At higher concentrations secretory capacity of PAH decreases) #### Clearance & Plasma Concentration - Clearance of most materials doesn’t change over a range of plasma concentration: - PAH: - Low plasma concentration – PAH secreted intensively - Plasma concentration↑ - secretory capacity of tubules↓ (Tm max) - clearance↓ (more PAH stays in blood) - At certain concentration all tubules have max secretion capacity, excretion doesn’t grow - clearance becomes constant at a low value - Inulin: - Plasma concentration doesn’t influence clearance - inulin only filtered. - Urea: - Clearance is lower than of Inulin & independent on concentration - unlimited Filtration capacity - Clinical - Tubular cell disease → urea recirculation is damaged → urea in blood↑ (uremia) - Glucose: - Normal plasma concentration - clearance=0 - freely filtered & completely reabsorbed (at proximal tubules only) - Clinical - glucose plasma level ↑ → tubules can’t reabsorb (Tm max) → glucose in urine (Diabetes) ### Extraction - Kidney's ability to eliminate a substance from the organism - Incoming substance amount in a. renalis should equal exiting substance amount in v. renalis - Incoming concentration should be higher than exiting concentration - Extraction can be referred to whole kidney or one glomerulus - Pa = Pv → E=0 - minimal extraction (entire substance appears on venous side, nothing gets into urine) - Pv = 0 → E=1 - maximal extraction (substance entering in arterial side doesn’t appear on venous side) - Renal extraction is usually < 1 (due to "resting" nephrons) ### Renal Plasma Flow (RPF) - Substance amount entering on artery = substance amount leaving on venous & urine side (flick principle) - Substance (PAH) for which Pv=0 so that: - Extraction=1 - RPF = Clearance ### Renal Blood Flow (RBF) - Volume of blood delivered to kidneys per time unit - RPF(PAH)=670 ml/min & Htc=0.44 RBF (PAH)=1200 mi/min ### Glomerular Filtration Rate (GFR) - Amount of filtrate produced per time unit by all nephrons by both kidneys (GFR=120 ml/min = 180 l/day) - Low GFR = low kidney function. - High GFR = high kidney function. - Under 80-250 mmHg mean arterial pressure - kidneys maintain value constant. - GFR can be measured by Inulin or creatinine: - Inulin: GFR = Cin=120 (human) | 50 (dog) | 65 (horse) | 70 (pig) | 75 (cow) - Creatinine: In most species, secreted to a certain extent (Ccreat > Cin) → inulin is favored for tests - Filtration capacity/Filtrate load (FL) – ultrafiltrated amount per time unit ### Factors of GFR: - Major changes of RBF don’t influence GFR substantially (autoregulation) - Glomerular pressure changes lead to similar yet reduced changes of GFR (due to autoregulation) - (extreme) Capsular pressure↑→ GFR↓↓ - Glomerular colloid osmotic pressure↑ → GFR↓↓ - (Pathogenic) glomerular membrane permeability ↓→ GFR↓ - Total filtration surface↓ (nephrectomy) → GFR↓ ## Transport Processes in the Proximal Tubule ### Types of Transport - Active: Transcellular – through the cell, need special channels/pump/carrier proteins - Passive: Paracellular ### General: - High transport capacity - 2/3 of water - 70% of filtered material is absorbed in proximal tubules - Main driving force: High pressure in peritubules - Intensive Paracellular reabsorption - urea, creatinine, bicarbonate – stay in tubule (don't reabsorb) ### Sodium Transport: - Secondary active transport of Anti-porter - letting Na according to electrochemical gradient into cell & H out of cell: - Channels passively let Na reabsorb according to electrochemical gradient - Main driving force of transport process - Na-K pump/ATPase (3Na-2K) - Amiloride can block this path (used in liver failure when water content is unbalanced) ### Bicarbonate Transport: - Second main job of proximal tubule: building bicarbonate: - Bicarbonate can’t flow freely into the cell, but its breakdown ingredients (H2O & CO2) can: - CO2: diffuses fully - H2O: diffuses partially - Bicarbonate is added to a luminal proton to form carbonic acid → which is broken down to H2O & CO2. - Luminal CA speeds up process (more than 80% HCO3 is broken down and transfer through) - HCO3 produced by IC CA goes into ISF via Na+-3HCO3 symport - Acetazolamide can block CA - Clinical - If HCO3 reabsorption inhibited → great Na+ & H2O loss → diuresis (increased urine formation) - Clinical – If HCO3 reabsorption inhibited → buffer capacity of blood↓ → blood becomes acidic with low pG pH * ### Chloride Transport: - Low pH in the lumen is a prerequisite for this process - Cl- acidic anion lumen antiporter moves Cl to cell & acidic anion from cell to lumen - Lumen acidic anion binds with H+ → forming free acid that goes freely into cell - Driving force of paracellular Cl transfer - HCO3 reabsorption increases Cl gradient - Cl moves passively - Clinical – If Cl remains in lumen → electric disbalance may be harmful for kidney ### Water Transport: - Paracellular: Peritubular oncotic pressure↑→ H2O to go into ISF - Transcellular: aquaporin type 1 channel (AQP1) – allows H2O into cell (along with Na & Cl ions) ### Glucose and Amino Acid Transport: - Glucose and Aa are withdrawn from tubules together with Na via secondary active symport maintained by Na-K ATPase: - Glucose and Aa each have their own Na symport carriers - Clinical - in diabetes mellitus, there is too much glucose, and it can’t be reabsorbed → extreme urination ### Urea, Proteins and Organic Anions/Cations: - Urea: - ~half of urea passively reabsorbed - Rest remains & help maintain osmotic layering of the kidney - Clinical - If Urea↓ in Car → protein absorption issue (possible liver failure) - Proteins: - Majority of protein that get into a lumen return to tubules by pinocytosis → continue to ISF as amino acids - Clinical - Protein should have a low % in urine - Organic Anions/cations: - Secreted to tubules ### Basis of their removal: - Na-K ATPase ## Transport in the Henle-Loop & the Distal Convoluted Tubule; Transport of Ammonia & Potassium ### Most Important Job: - Generation of hyperosmotic renal medulla (Prerequisite for kidney to concentrate urine) - Meaning: increasing the amount of ions present in the solution. ### Loop of Henle: - Descending Thin Limb (DTL): - Little secretory & absorptive ability - Ascending Thin Limb (ATL): - High permeability - Thick Ascending Limb (TAL): - 25% of filtered substances are reabsorbed in the thick ascending limb (TAL) - Important symport – furosemide sensitive Na-K-2CI (Driving force of symport – Na-K ATPase) - Furosemide - can block this path - TAL is impermeable for H2O & urea → lumen is hypoosmotic as a result ### Distal Convoluted Tubule (DCT) - Na+, Cl symport (absorbs additional 5% of filtered Na on luminal side) - Ca2+- in case of low blood Ca (hypocalcemia) → parathyroid hormone (PTH) dependent reabsorption begins: - PTH → Ca reabsorption↑→ increase blood Ca level - Calcitriol increases bone break-down → therefore increase reabsorption of Ca in the blood - Calcitonin → suppresses osteoclast activity → decreasing systemic Ca by increasing Ca urine excretion ## Ammonia Transport ### Proximal Tubule: - Goal: metabolic formed H⁺ removal (Too many protons produced in the acid-base equilibrium process) - Glutamine is broken down to ammonia by enzyme → secreted to lumen & united w/ excess H+ ions → NH4+ excreted to thin ascending limb of Henle loop as sulphate or ammonium sulphate (=non-titratable acidity) - The salt formation (NH4+) ensures pH doesn't get acidic during excretion – to not damage urinary tract epithelium ### Henle Loop: - Goal: NH4+ taken up to cells by active K-NH4+ exchange - Lumen is impermeable to ammonia; therefore ammonia moves to interstitium ### DTL: - NH4+ is actively taken up from interstitium by collecting tubules → excreted outside (of body or back to lumen on prox'?) ## Potassium Transport - A 0.1% increase in plasma K+ → aldosterone secretion (from adrenal gland) K+ secreted to distal tubule & to urine: - 100% of K is ultrafiltrated - PCT: 1st active K reabsorption (K-CI cotransporter) - PST: K migration from interstitium into lumen (recirculation) - DTL: filtered K is reabsorbed (some remains in lumen) - TAL: 2nd active K reabsorption into interstitium (recirculates into the lumen) - CCT: mineralocorticoid dependent secretion of K+ with Na+ reabsorption ## Transport at the Distal Connective Tubule & at the Collecting tubule; Water Transport ### Distal Nephron: - Connecting tubule (CNT) - Cortical collecting tubule (CCT) - Medullary collecting tubule (MCT) ### Where hormonally regulated processes take place - No more K+ absorption - Until this point, cells were unified, but now they are divided into two groups: - Principal (CNT): - Na+-K+ balance (main Na reabsorbing cells & aldosterone action site) - Driving forces: Na-K pump & luminal Na & K channels - K - passive transport in both directions (luminal - secretion, basolateral - reabsorption) - Na↓ - can be inhibited by amiloride (diuretic - more peeing, maintain Na from getting to low level) - All the above is aldosterone dependent - If K is in excess in blood → aldosterone produced more → luminal channels → Na reabsorption → K secretion - Addison's disease - low Aldosterone level - Cushing syndrome – high Aldosterone level - Intercalated (CCT, MCT): - Most important for acid/base regulation - Intercalated cells type A: - Defense against acidosis - secretion of H+ / reabsorption of bicarbonate - H+ of the cell’s water is forwarded to lumen by electrogenic H-K ATPase pump - Remaining OH joins to CO2 (from blood) by CA to form HCO3 that is reabsorbed in blood by CI-HCO3 antiporter - Intercalated cells type B - Defense against alkalosis – reabsorption of H+ / secretion of bicarbonate: - H+ of the cell’s water is forwarded to blood by electrogenic H-K ATPase pump - Remaining OH joins to CO2 (from blood) by CA to form HCO3 that is secreted to lumen by CI-HCO3 antiporter ### Water Transport - Water transport in the distal tubules (CNT, CCT, MCT) is hormonally regulated: - Transport is linked to AQP2 (aquaporin-2) - water channel protein of principal cells: - This protein is bound to microsomes (endosomes) inside the cells - Under ADH effect → water channels migrate to luminal pole (facilitating water movement based on osmotic conditions) - ADH mediated H2O transport [important for midterm] - ADH (antidiuretic hormone) or vasopressin ensure isoosmosis & water retention - ADH: produced in hypothalamus → reaches neurohypophysis → released when blood osmotic concentration goes over 300 mosmol/l (too much salt in blood) → high water retention - Basolateral V2 receptors of collecting ducts stimulate luminal surface appearance of AQP2 → water reabsorbed by osmotic gradient - BP↑→ inhibits ADH further production ## Osmotic Gradient and Osmotic Capacity of the Kidney ### Factors creating the osmotic gradient: - Na reabsorption - Driving force - active Na reabsorption of the TAL (Na-K-2Cl pump) - Urea - Its circulation stabilizes hyperosmosis by creating a "layering" effect - Countercurrent multiplication - A mechanism that also maintains a status quo (osmotic pressure) in the Henle loop - Vasa recta - maintains medullary hyperosmosis ### Osmotic Gradient Effects: - Isosmotic fluid gets to PCT with blood plasma (main osmotic particle: Na+, Cl-) - PCT & DTL - permeable to water, but slightly permeable to salt and urea. Therefore: - water comes out from the tubule in the direction of the higher interstitial osmotic gradient - Urea & salts can’t come out in the same route - Result : DTL osmolarity of lumen↑ and reaches that of interstitium - ATL - impermeable to water, but permeable to NaCl & urea. - NaCl diffuses passively to the interstitium (but can’t be compensated for with water movement) - Result: tubule lumen liquid becomes diluted - TAL - impermeable to water, but actively reabsorbs large quantity of NaCl. - The closer to cortex → osmolarity↓ - DCT: - Beginning - "diluting" segment - osmolarity of tubular fluid can be reduced to 200 mosmol/l. - End - ADH-dependent mechanisms start ### Osmotic Capacity: - Urine concentration/dilution is characterized by total amount of osmotically active particles excreted - Osmotic clearance - amount of plasma cleared of all osmotically active particles per unit time. - measuring urine osmolarity ratio allows for extent of maximal water conservation to be measured - Free water clearance - minute urine volume & osmotic clearance differences expressing degree of dilution - Osmotic plateau - maximal concentrating capacity (proportional to number of juxtamedullary glomeruli) ### Why all these colors?: - Segment name in violet - Diuretic name in pink - Reabsorption in red - Secretion in green - Percentage in blue - Hormone in orange ### Water Molecules Movement: - Water molecules are moved from high to low blood filtrate pressure. - Glomerular BP is opposed by osmotic pressure (glomerular oncotic pressure - colloids that cannot leave capillaries). - Factors creating an osmotic gradient: - H2O moving to hyperosmotic interstitium - Na+ repetitive reabsorption - Interstitial hyperosmosis (Na+, Cl- & urea). - Most important (happening in parallel): - Increased Na transport (lumen → interstitium) at TAL with water transport inhibition - Decreased Na transport (lumen → interstitium) at DTL with water transport - Urea countercurrent multiplier: stabilizes as well. It is reabsorbed in PCT, DTL & MCT, but can't leave at other parts. - Vasa Recta: shape of vasa recta, running along perpendicularly with tubules (parallel with osmotic gradient) allows for maintenance of osmotic gradient, if it wouldn’t run parallel, osmotic equivalents of the medulla would be washed out. - Medullary cells don’t shrink in hyperosmotic environment due to inert osmolytes (betain, sorbite and glycerine-derivatives) that don’t metabolize. ## Neural and Autoregulation of Renal Circulation ### Intrinsic & Extrinsic Regulation: - Autoregulation (mechanism works in the benefit of the kidney) - Myogenic reflex: - Renal blood flow & glomerular filtration rate are regulated by adaptive contraction of a-/efferent arteriole - BP↑ - afferent arteriole vasoconstrict & efferent arteriole vasodilate (papaverine, acetylcholine - block) - BP↓ - afferent arteriole vasodilate & efferent arteriole vasoconstrict - Tubuloglomerular feedback: - GFR↑ - distal tubular pressure & NaCl concentration↑ ➔ basolateral release of adenosine from macula densa cells → adenosine initiates G-protein cascade in mesangial cells → mesangial cells' endoplasmic reticulum creates Ca ions that travel to JGA cells (via gap junctions) & nearby smooth muscle cells → Ca stimulate release of Renin granules from JGA cells & vasoconstriction from smooth muscle cells → GFR ↓↓↓ - GFR↓ - no distal tubular pressure & NaCl concentration ↓ → no renin release & smooth muscles dilate → GFR ↑↑ - The juxtaglomerular apparatus cells regulate renal blood flow & GFR. - It is found between afferent arteriole & distal convoluted tubule of the same nephron. - It consists of swollen smooth muscle & myoepithelial cells of both afferent and efferent arteriole. - BP↓↓ → produce Renin → BP increases via Renin-Angiotensin-System (RAS) ### Neural (hormonal) Regulation (mechanism works in the benefit of the vital organs) - Cortical vessels innervated by sympathetic (not in medulla): - Pressor reflex: BP↓ → sensed in sinus caroticus & aorta↓ → CNS: - a1-adrenergic receptors of smooth muscle cells → norepinephrine release → peripheral vasoconstriction - ẞ1-adrenergic receptors of JGA cells → Ca produces to release renin to bloodstream - Blood redistribution: increased muscle activity / shock / pain → renal ischemia → blood redistribution - Sympathetic - Runs to a-adrenergic receptors of v. afferent - Afferent arterioles vasoconstriction - GFR↓↓ - Parasympathetic - Not yet understood - Pain-sensing fibers - Senses stretching of capsule ## Osmoregulation, Antidiuretic Hormone (ADH) ### ADH: - Trigger: blood volume↓↓, dehydration → salt dissolved in blood concentration↑→ hyperosmosis - Hypothalamus receptors react to pressure change → neurohypophysis of pituitary gland releases more ADH. - At the same time, thirst center in hypothalamus stimulates thirst sensation. - Result: significant water retention. - The body tries to establish osmotic pressure & body temp’ first - hence why salt concentration is the most important trigger (even more than blood volume decrease). ### General Factors: - Plasma hyperosmosis detected by Osmoreceptors of hypothalamus (primary factor) - Stress, Pain ### Effects: - AQP2 expression → water retention - V1 receptors stimulation → Vasoconstriction (in case of bleeding) - V2 receptors on basolateral side of collecting ducts stimulate luminal surface appearance of AQP2 channels → reabsorption ### Inhibitors: - BP↑ detection by baroreceptors - Central & atrial ANP production ## Osmoregulation - Primary aim - Osmotic hemostasis maintenance - This happens on expense of isovolemia (body can cope longer with volume change than osmotic change) - Frequent water loss require maintenance of Isosmosis & isovolemia (which require wide range of urine volume) - Since kidney itself can’t adapt in one step - explains development of osmotic layering of kidney tissue - Layering enables quantity & osmolarity change of urine with small energy input in a rapid and high capacity reaction - Countercurrent multiplier & exchanger responsible for creation & maintenance of this layering - Urine osmolarity & volume regulation is fundamentally dependent on hormonal & neural mechanisms ### Hydropenia: - little, hyperosmotic urine production. ### Osmotic Load: - blocked tubular H2O reabsorption → osmotic diuresis (increase urination due to too much osmotic pressure) ### Hyperosmosis Regulation: - Hyperosmosis → EC & IC are balanced (in minutes)- hyperosmotic isovolemia → Hypothalamic osmoreceptor sensing → blood ADH level↑ AQP2 increase in distal tubules → reabsorption / water retention ⇒ isosmotic hypervolemia (solved long term) - Can be created by: - Substances that don’t reabsorb after filtration (mannit-artificial ingestion, glucose-diabetes) - Substances that reabsorb after filtration (sodium) ### Hypoosmosis regulation: - Salt loss/reduced intake → ADH inhibition → less water retention → hypoosmotic hypovolemia - isosmotic isovolemia ### Isoosmosis regulation: - ADH role in maintaining isoosmosis (as proved in following examples) - Without endocrine mechanisms → kidney produces hypoosmotic urine (ADH application readjusts isoosmosis) - If hypothalamic ADH secreting locus is damaged → hypoosmotic urine - Increased diuresis can be blocked with ADH ## Hypovolemia Regulation: - Hypervolemia → RAS activation → Angiotensin-Il synthesis ↑ (vasoconstriction, aldosterone stimulation, dipsogenic effect) → Aldosterone synthesis ↑ → distal tubules Na reabsorption ↑ → water retention → isovolemia ## Hypervolemia Regulation: - Hypervolemia → RAS inhibition → isosmotic fluid loss → normal conditions restore → isovolemia - ANP stimulation (Na excretion, ADH inhibition) ## Volume Regulation in the Kidney; Renin-Angiotensin System, Aldosterone and ANP ### Renin-Angiotensin System: - Trigger: hypovolemia↓ or Na↓ - Renin synthesis from Juxtaglomerular cells while, Parallelly, angiotensinogen produced in liver. - Angiotensinogen becomes Angiotensin-I in the presence of Renin. - Angiotensin converting enzyme (ACE) produced in kidneys & lungs produces Angiotensin-II from Angiotensin-I. - ACE can be inhibited by Captoprile. - Angiotensin-II: - Pressor effect (smooth muscle of vascular system): vasoconstriction↑ (x8-x10 stronger than epinephrine) - Direct Na reabsorption↑ (kidney) – water reabsorption↑ → stroke volume↑→ BP↑ - Indirect Na reabsorption↑ (adrenal gl.) - Aldosterone release → Na reabsorption↑→ water reab'... → BP个 - ADH release (pituitary gland) → water reabsorption↑ stroke volume↑→ BP个 - Dipsogenic effect - stimulate thirst → water & salt intake↑ - Once no longer needed → breaks down to Angiotensin III & also triggers synthesis of Aldosterone - Result: higher water & Na retention in the body (mechanism against hypovolemia) ### Atrial Natriuretic Peptide (ANP): - Produced, stored & released by atrial muscles ### Stimulation factors: - atrial stretch (primarily) - salt load - fluid load ### Function: - anti-hypervolemic effect – salt excretion↑ & water retention ↓↓ ### Effects: - inhibit Na+ retention in collecting ducts - increase RPF (consequently increasing GFR) - inhibit renin secretion → inhibit RAS - direct ADH synthesis inhibition (ADH tries to retain Na) - decrease aldosterone secretion ### Aldosterone: - Produced by zona glomerulosa of adrenal cortex - Stimulation factors: - hyperkalemia (K+) in plasma sensed by z. glomerulosa cells (less than 0.1 mmol/l increase will trigger) - EC volume or BP↓ sensed by RAS system→ increases aldosterone synthesis via angiotensin-II - CRH triggers synthesis of ACTH which triggers aldosterone synthesis - Role: - The only regulator of K+ excretion (keeping it within narrow ranges) - A factor of Na+ & water reabsorption induced by angiotensin-II - Salt hunger increase (CNS) - Note: while ADH primarily assists in plasma osmolality, aldosterone regulates entire Na content of the body (EC) ### Action Site: - Main effect site - distal tubule & cortical section of the connecting & collecting ducts. - Binds to IC receptors → enters nucleus → elicits expression of Na+/K+ ATPase pump & channels - Additional sites - salivary & sweat gland, epithelial cells of large intestine ### Volume Regulation: - Normal status: NaCl uptake & excretion are balance - Extra salt load: - Mechanism – hyperosmosis → thirst sensation (Verney) → drinking → isoosmosis - 1-2 days for elimination, but extra salt & water stay in EC space → hypervolemia - Extra salt & water elimination occur gradually - Extra water intake effect on circulation: - Blood volume↑, arterial pressure↑, stimulation of baroreceptors - Peripheric vasodilation & oncotic pressure↓ (due to hemodilution) - Fluid leaves circulation to interstitium (=edema) ## The Urinary Tract and the Process of Urination ### Urinary Tract: - Upper urinary tract: - Including: calices, renal pelvis, ureters - Rhythmical contraction of calyx moves urine to renal pelvis - Ureter peristalsis moves urine at a speed of 2-3 cm/s - Ureter enters bladder in an angle that blocks any way for urine backstream to kidney - Normally there is no urinal reflux (in case of urination difficulty, retrograde flow & infection may occur) - Lower urinary tract – bladder (& urethra) - Its wall consists of special smooth muscle (M. detrusor) & elastic fibers that react to stretch → relaxation - The growing stretch slightly stimulates until at one point a sudden mechano-receptors activity increase → urination is induced ### Urination Process: - Emptying of bladder is controlled by urinary center in pons (input received from mechanoreceptors of bladder). - Execution done by following systems: - Lumbal (sympathetic) - Sacral (parasympathetic) - Somatic motor (abdominal muscles, perineum, outer sphincter) ### Filling Phase: - Sympathetic presynaptic inhibits Parasympathetic system ((m-ACh-R) responsible for contracting bladder wall) - Sympathetic (ẞ2 receptors) relax m. detrusor & contract (via a1 receptors) the bladder neck smooth muscles - Increased AP release (n. pudendus, n-ACh-R) contracts outer muscles ### Urination (=micturition): - During urination, mechanoreceptor activity ↑→ parasym’ activation in pons ↑→ somatic & symp’ inhibition. - Bladder wall contracts, sphincter relaxes, urination begins. ### Full Process: - Avian kidney: - Max’ urinary osmolarity lower than terrestrial mammals. - Some nephrons lack Henle loop (reptilian-type nephrons), others have it (mammalian-type nephrons). - Concentrating capacity of kidney in different avian species depend upon number of mammalian-type nephrons. - Birds don't have urinary bladder - urine flows into cloaca. - Moreover, antiperistaltic contractions transports cloacal content back to the colon and ceca. - Therefore, salt & water content of avian urine is finally adjusted by the cloaca & large intestine. - Nitrogen is mostly excreted by tubular secretion as uric acid (soft, white color covering birds' faeces). - Most birds have salt glands pair that empty secretion to nasal cavity (largest glands in birds consuming seawater). - The salt glands have one of the most efficient ion transport system known. | Trigger | RAS | ADH | ANP | K+ | ALD | |:--------------------|:-------------------|:--------------|:--------------|:----------------|:----------------| | | VOLUME↓/Na↓↓ | Na↑/ | VOLUME↑ (BP↑) | EC VOLUME/Na↓ | BP↓ | | | | OSmotic pressure↑| | | | | | | VOLUME↓ | | | | | Effect | VASOCONSTRICTION↑| AQP2↑ | Na↑ (excretion)| K+↓ | Na↑ | | | BP↑ | H2O↑ | H2O↓ | | | | | ALD↑ | | BP↓↓ | | | | | ADH↑ | | ALD↓ ADH↓↓ | | | | | | | | | Na↑ | | Effect | Hypoosmosis | Hyperosmosis | Hypovolemia | Hypervolemia | |:------------|:-------------|:-------------|:------------|:---------------| | | ADH ↑ | ADH ↓↓↓ | RAS ↑ | RAS ↓↓↓ | | | AQP2 ↑ | AQP2 ↓ | ALD ↑/ADH↑ | ALD/ADH↓↓ | | | H2O ↑ | H2O ↓ | Na reabsorption ↑ | ANP ↑ | | | | | H2O ↑ | Na ↓↓↓ → H2O ↓ | | Solution / Result| Isovolemia | Isovolemia | Isovolemia | Isovolemia | | | Hypovolemia | Hypervolemia | | | | | Main objective is | | | | | | restoring isosmosis | | | | | | (hypovolemia is a | | | | | | by-product of | | |