Physiology Urinary System Lecture 2 PDF

S 1 L1 PHYSIOLOGY Urinary System Lecture 2 Explained by : Fadhal Allah Najhe Edited by : Hussain Jawad Objectives I. Physiologic control of glomerular filtration (GFR) and renal blood flow (RBF) II. Renal Tubu...

S 1 L1 PHYSIOLOGY Urinary System Lecture 2 Explained by : Fadhal Allah Najhe Edited by : Hussain Jawad Objectives I. Physiologic control of glomerular filtration (GFR) and renal blood flow (RBF) II. Renal Tubular Reabsorption and Secretion III. Reabsorption and Secretion along different parts of the Nephron Physiologic control of glomerular filtration (GFR) and renal blood flow (RBF) GFR is mainly determined by glomerular hydrostatic pressure and the glomerular capillary colloid osmotic pressure (prev. lecture). These variables, in turn, are influenced by: 1-Extrinsic mechanisms 2-Intrinsic mechanisms 3-Autoregulation of GFR and RBF 1-Extrinsic mechanisms: Extrinsic mechanisms: Neural control and hormonal control - these extrinsic mechanisms can override renal autoregulationand decrease the glomerular filtration rate when necessary. 1-Sympathetic nervous system activation decreases GFR: ❑ The afferent and the efferent renal arterioles are innervated by sympathetic nerve fibers. ❑ For example, if you have a large drop in blood pressure such as those elicited by the severe haemorrhage, your nervous system will strongly stimulate the renal sympathetic nerves can constrict the afferent arteriole and decrease RBF and GFR (reducing urine production).Moderate or mild sympathetic stimulation has little influence on RBF and GFR. 1-Extrinsic mechanisms: 2- Hormonal control of GFR and renal circulation: A- Norepinephrine (Nep), epinephrine (Ep), and endothelin: Nep. and Ep. ❖ hormones (releasefrom adrenal medulla) constrict afferent and efferent arterioles, causing decrease GFR and RBF. ❖ The Nep. and Ep. influence on GFR is little, except under conditions associated with strong activation of the sympathetic nervous system such as severe hemorrhage. ❖ Endothelin is a peptide act as vasoconstrictor, that can be released by damaged vascular endothelial cells of the kidneys inmany disease states associated with vascular injury (such as acute renal failure, and pregnancy toxemia), causing decreased GFR. 1-Extrinsic mechanisms: 2- Hormonal control of GFR and renal circulation B- Angiotensin II: ▪ A powerful renal vasoconstrictor, Ang II can be considered to be a circulating hormone and a local (autacoid or paracrine hormone) because Ang II is formed in the kidneys and in the systemic circulation. ▪ Receptors for Ang II are present in all blood vessels of the kidneys, it constricts the afferent and efferent arterioles. ▪ The efferent arterioles are highly sensitive to Ang II. ▪ Increased Ang II levels induced constriction of efferent arterioles, and prevent decreased glomerular hydrostatic pressure (low Na+ diet) or volume depletion, which tend to decrease GFR. 1-Extrinsic mechanisms: 2- Hormonal control of GFR and renal circulation B-Angiotensin II: ❖ Increased angiotensin II helps maintain GFR and normal excretion of metabolic waste products(urea and creatinine ). ❖ Increases tubular reabsorption of sodium and water and restores blood volume and blood pressure. ❖ The preglomerular blood vessels (afferent arterioles), appear to be relatively protected from angiotensin II-mediated constriction in most physiological conditions associated with activation of the renin-angiotensin system, such as a low Na+ diet or reduced renal pressure (due to renal artery stenosis), this protection is due to the release of vasodilators(prostaglandins and nitric oxide), which counteract the vasoconstrictor effects of angiotensin II in these blood vessels. 1-Extrinsic mechanisms: 2- Hormonal control of GFR and renal circulation C- Endothelial-derived Nitric Oxide: normally it maintains vasodilation of the kidneys, decreases renal vascular resistance and increases GFR, so allows the kidneys to excrete normal amountsof sodium and water (impaired nitric oxide production blood pressure, such as in patient withatherosclerosis, damage of the vascular endothelium and impaired nitric oxide production maycontribute to increased renal vasoconstriction and elevated blood pressure). 1-Extrinsic mechanisms: 2- Hormonal control of GFR and renal circulation D-Prostaglandins and bradykinin: ❖ are hormones and autacoids that cause vasodilation, decrease renal vascular resistance, increase renal blood flow and GFR. ❖ Its importance appears by opposing vasoconstriction of afferent arterioles (by inhibiting the sympathetic nerves) and prevents excessive reductions in GFR and renal blood flow. ❖ (So in volume depletion as severe hemorrhageor after surgery, the administration of non-steroidal anti-inflammatory agents NSAIDs, such as aspirin that inhibit prostaglandin synthesis may cause significant reductions in GFR). 2-Intrinsic mechanisms: Renal autoregulation - the kidney itself can adjust the dilation or constriction of the afferent arterioles , which counteracts changes in blood pressure. This intrinsic mechanism works over a large range of blood pressure, but can malfunction if you have kidney disease. There are 2 defence lines buffer the effects of spontaneous changes in GFR on urine output are:The first line is the renal autoregulatory mechanisms, especially tubuloglomerular feedback.The second line is the glomerulotubular balance (discussed later). 3- Autoregulation of GFR and RBF Autoregulation is the intrinsic feedback mechanisms of the kidneys normally keep the renal blood flow and GFR relatively constant, despite marked changes in arterial blood pressure which is independent of systemic influences (For instance, a decrease in arterial pressure toas low as 75 mm Hg or an increase to as high as 160 mm Hg changes GFR only a few percentage points). These autoregulation mechanisms are: 1-Tubuloglomerular feedback 2-Myogenic autoregulation of RBF and GFR 3. Other factors : A. Chronic high protein intake B. Glucose intake 3- Autoregulation of GFR and RBF 1-Tubuloglomerular feedback: This feedback depend on special anatomical arrangements of the juxtaglomerular complex, that consists of macula densa cells which is a specialized group of epithelial cells in the initial portion of the distal tubule that comes in close contact with the afferent and efferent arterioles that have juxtaglomerular cells in their walls. The macula densa cells contain Golgi apparatus, which are intracellular secretory organelles directed toward the arterioles. 3- Autoregulation of GFR and RBF 1-Tubuloglomerular feedback The tubuloglomerular feedback mechanism starts as GFR decreases lead to slow the flow rate in the loop of Henle and increased reabsorption of Na+ and CL- ions in the ascending loop of Henle and reducing the concentration of sodium chloride (NaCl) at the macula densa cells which initiates a signal from the macula densa that has two effects that act together to control GFR : (1) An afferent arteriolar vasodilator feedback mechanism:the signal dilates the afferent arterioles, which raises glomerular hydrostatic pressure and return GFR toward normal. 3- Autoregulation of GFR and RBF 1-Tubuloglomerular feedback (2) An efferent arteriolar vasoconstrictor feedback mechanism: the signal increases rennin release from the juxtaglomerular cells of the afferent and efferent arterioles(which are the major storage sites for rennin). Renin acts as an enzyme to increase the formation of angiotensin I, which is converted to angiotensin II. Finally, the angiotensin II constricts the efferent arterioles, increasing glomerular hydrostatic pressure and returning GFR toward normal. 3- Autoregulation of GFR and RBF 2-Myogenic autoregulation of RBF and GFR: Increase arterial pressure lead to stretch vessels wall which allows increased calcium ions movement from the extracellular fluid into the cells, lead to contraction of the vascular smooth muscle and raising vascular resistance which prevent excessive increases in renal blood flow and GFR. 3- Autoregulation of GFR and RBF 3. Other factors : A. Chronic high protein intakeHigh Protein intake cause ↑ RBF and ↑ GFR :↑ a.a, stimulate a.a/Na+ reabsorption in proximal tubule (by cotransport),this leads to↓ Na+ in macula densa, and ↓ RA, and so ↑ RBF & GFR, allowingNa+ excretion to restore normal value and excretion of waste products of protein metabolism, such as urea. B. Glucose intake : same mechanism. High blood glucose levels in uncontrolled diabetes,cause ↑ RBF and↑ GFR: due to glucose/Na+reabsorption along in the proximal tubule &decreases Na+ delivery to the macula densa, which elicits a tubuloglomerular feedback. 3- Autoregulation of GFR and RBF 3. Other factors : An opposite occurs when proximal tubular reabsorption is reduced :by damage, metals poisoning (mercury), and large doses of drugs; lead to ↓ sodium chloride (NaCl),and large amounts of NaCl are delivered to the distal tubule and, without appropriate compensations(as tubuloglomerular feedback–mediated renal vasoconstriction) would quickly cause excessive volume depletion. Renal Tubular Reabsorption and Secretion The urine is formed in the nephron by the processes of glomerular filtration, selective reabsorption and tubular secretion; Urinary excretion = Glomerular filtration – Tubular reabsorption + Tubular secretion 1-Tubular secretion: it is the process by which the substances are transported from blood into renal tubules. It is also called tubular excretion. Substances secreted in different segments of renal tubules are: 1. Potassium is secreted actively by Na+- K+ pump in proximal and distal convoluted tubules and collecting ducts, 2. Ammonia is secreted in the proximal convoluted tubule, 3. Hydrogen ions are secreted in the proximal and distal convoluted tubules. Maximum hydrogen ion secretion occurs in proximal tubule. 2-Tubular reabsorption: It is the process by which filtered water and solutes from the tubular lumen in to the interstitial fluid of renal medulla, then move into the blood in peritubular capillaries (as shown in the figure below). Large quantity of water (more than 99%), electrolytes and other substances are reabsorbed by the tubular epithelial cells. It is mainly occurs in the proximal tubule and the Loop of Henle. Tubular reabsorption is known as selective reabsorption because the tubular cells reabsorb only the substances necessary for the body. Essential substances such as glucose, amino acids, andvitamins are completely reabsorbed from the renal tubule, so the urinary excretion rate is essentiallyzero, in contrast, many ions in the plasma are reabsorbed depending on the body's needs. 2-Tubular reabsorption: Where as unwanted substances like metabolic waste products (urea, and creatinine) are excreted through urine. Tubular reabsorption is highly selective, unlike glomerular filtration, which is nonselective(essentially all solutes in the plasma are filtered except the plasma proteins or substances bound to them). 2-Tubular reabsorption: Substance filtration rate = Glomerular filtration rate x substance plasma concentration. This calculation assumes that the substance is freely filtered and not bound to plasma proteins. Forexample, if plasma glucose concentration is 1 g/L, the amount of glucose filtered each day is about180 L/day × 1 g/L, or 180 g/day. Because virtually none of the filtered glucose is normally excreted,the rate of glucose reabsorption is also 180 g/day. 2-Tubular reabsorption: Solutes are transported either through the tubular cell mem. called a transcellular pathway (passive or active transport), or through the space between the cell junctions called a paracellular pathway (passive),while the water is transported through the cells and between the tubular cells by Osmosis, then in to the renal interstitial fluid and then through the peritubular capillary membrane to the blood byUltrafiltration (bulk flow) that is mediated by hydrostatic and colloid osmotic pressures. Passive diffusion: is the movement of molecules along the electrochemical gradient. This process doesn’t need energy. The substances reabsorbed by passively are chloride, urea and water. 3-Active Transport is the movement of molecules against the electrochemical gradient. It needs liberation of energy which is derived from ATP. The substances reabsorbed actively from the renal tubule are sodium, calcium, potassium, phosphates, sulfates, bicarbonates, glucose, amino acids , ascorbic acid, uric acid, and ketone bodies. There are 2 types of active transport: ▪ Primary active transport ▪ Secondary active transport 3-Active transport 1-Primary active transport Primary active transport: Energy source is directly from the hydrolysis of adenosine triphosphate(ATP) by membrane-bound ATPase, ATPase also binds and moves solutes across the cell membranes. The primary active transporters in the kidneys that are known include; Na+- K+ ATPase, hydrogenATPase, H+- K+ ATPase, and Ca+ ATPase. The Na+, K+ ATPase pump a good example of a primary active transport system is the reabsorption of Na+ ions across the proximal tubular membrane; it involves the following steps: 3-Active transport 1-Primary active transport Steps 1.Na+ is transported across the basolateral membrane from low concentration at the renal tubular cell to high concentration at the interstitium (interstitial fluid) byNa+- K+ ATPase pump and K+ is transport vice versa.This leading to; A/ Low intracellular Na+ and high intracellular K+conc. B/ Creates a net negative charge within cell.These both reasons lead to: 3-Active transport 1-Primary active transport Steps 2. Na+ passive diffuses (from high to low concentration)across the luminal membrane (brush border) into the renal tubular cell. The negative intracellular charge attracts the positive Na+ ions from the tubular lumen into the cell. 3. Na+, water, and other substances are reabsorbed from the interstitial fluid into the peritubular capillaries by ultrafiltration. 3-Active transport 2-Secondary active transport Secondary active transport: It utilizes energy indirectly from energy source (Na+- K+ ATPase pump). ❑ When two or more substances combine with a carrier protein, as one of the substances (e.g. Na+) diffuses to the low concentration in the cell ❑ the energy released from this transport is used to drive another substance(e.g. glucose or amino acid) from its low to high concentration, ❑ Sodium glucose co-transporters (SGLT2and SGLT1) are located on brush border of proximal tubular cells, ❑ 90% of glucose is reabsorbed by SGLT2 in early part of proximal tubule, and 10% by SGLT1 in latter part, because Na+ and glucose are moved in the same direction called Na+- glucose (or amino acid) symporters.  3-Active transport 2-Secondary active transport ❑ Glucose and amino acids exit the cell across the basolateral membranes by facilitated diffusion with help of glucose transporters (GLUT2). ❑ Secondary active secretion into the tubules:e.g. Na+- H+ exchanger. It happens when substances are secreted into the tubules (H+) by secondary active transport as counter- transport (opposite direction) with Na+, so called Na+- H+ antiporters. 4-Pinocytosis Pinocytosis: is an active transport for reabsorption of proteins, especially at the brush border of proximal tubule (protein invagination into tubule cell and digested into amino acids then reabsorbed). 5-Transport maximum Transport maximum (Tm or Tmax): describes the maximum rate at which a system is able to transport a solute. ❖ It thus predicts the phenomenon of saturation; below and up to the transport maximum, the amount of solute transported increases proportional to the concentration. ❖ However , once the transport maximum is reached, and the system is saturated, increases in concentration are not matched by further increases in transport.  5-Transport maximum ❑ Normally, all filtered glucose is reabsorbed in the proximal tubule, glucose doesn’t appear in urine. ❑ In the adult human, the tubular transport maximum for glucose averages about 375 mg/min. ❑ where as the filtered load of glucose is only about 125 mg/min, according to the following equation;Filtered load of substance = GFR (125 ml/min) Χ plasma concentration of substance (glucose conc.=1mg/ml). ❑ However, when the filtered load of glucose above 375 mg/min (un controlled diabetes mellitus), plasma concentration of glucose rises above 200 mg/100 ml (2mg/ml), and the filtered load = 250 mg/min, a small amount of glucose begins to appear in the urine (glucosuria), this point termed the threshold for glucose.  5-Transport maximum ❖ Appearance of glucose (at threshold) in urine occurs before the transport maximum ❖ The reason is that not all nephrons have the same transport maximum for glucose , and some of the nephrons therefore begin to excrete glucose before others have reached their transport maximum. ❖ 375 mg/min is the transport maximum for the kidneys is reached when all nephrons have reached their maximal capacity to reabsorb glucose. 5-Transport maximum ✓ Some substances that are actively reabsorbed (such as sodium) do not have a transport maximum ✓ because their rate of transport depends on the electrochemical gradient and time that the substance is in the tubule, which in turn depends on the tubular flow rate ✓ transport of this type is referred to as gradient-time transport. 5-Transport maximum ✓ Water is high permeability and rapidly reabsorbed (by osmosis) in proximal tubule and descending loop of henle ✓ Due to the presence water channel (aquaporin) and the tight junctions between the epithelial cells ✓ In contrast ascending loop, there is no reabsorption. ✓ As well as, the last parts of tubules(distal and collecting), water cannot move across the tight junctions by osmosis but depend on the presence or absence of antidiuretic hormone (ADH). 5-Transport maximum Chloride Cl- (negative charge) is reabsorbed passively due to: 1-Electrical gradient: the active transport of Na+ (positive charge) leaves the tubular lumen negatively charged compared with the interstitial fluid. This causes Cl- ions to diffuse passively through the paracellular pathway. 5-Transport maximum Note: In all nephron segments, exception of theloop of Henle, the tubular lumen (negative charged)compared with the interstitial fluid. 2-Concentration gradient: after water reabsorbedby osmosis, the Cl- concentrates in the tubularlumen, and thus cause Cl- diffusion. 3-By secondary active transport as co-transport of Cl- with Na+across the luminal membrane.  5-Transport maximum ❖ Urea is primary end product of protein catabolism,50% passively reabsorbed from the proximal tubule due to concentration gradient after water osmosis. Urea reabsorption is facilitated (by urea transporters) in some parts of the nephron, especially the inner medullary collecting duct; one of urea transporters is activated by ADH. ❖ Creatinine is an end product of creatine metabolism, it is an even larger molecule than urea and essentially impairment to the tubular membrane. Therefore, almost none of the creatinine that is filtered is reabsorbed, so all creatinine filtered is excreted in the urine. Reabsorption and Secretion along different parts of the Nephron 1-Proximal tubular reabsorption ❑ The proximal tubule is the major site for reabsorption of glucose, amino acid, several krebs cycle intermediates. ❑ It is the site of greatest Na+ and H2O, about 65% of the filtered load of Na+ and H2Oand a slightly lower percentage of filtered Cl-are reabsorbed by the proximal tubule before the filtratereaches the loop of Henle. ❑ The osmolarity remains constant (isotonic, 300 mOsm/L), along theproximal tubule because H2O reabsorption of the proximal tubules proportional to Na+ reabsorption. 1-Proximal tubular reabsorption The high capacity of the proximal tubule reabsorption results from its special epithelial cell characteristics, as following: 1- Highly metabolic. 2- Have large numbers of mitochondria for active transport. 3- Have an extensive brush border on the luminal (apical) side of the membrane and have extensive labyrinth of intercellular and basal channels which provide an extensive membrane surface area on the luminal and basolaterial sides of the epithelium. 4-The brush border is loaded with carrier protein. 1-Proximal tubular reabsorption The reabsorption and secretion of the proximal tubule as follow: ❑ In the first half of the proximal tubule: Na+ isco-transport along with glucose, amino acid and other solutes. ❑ In the second half of the proximal tubule: a little glucoseand amino acids remain to be reabsorbed from its lumen,while Na+ is reabsorbed mainly with Cl-as high Cl- concentration ❑ Others as HCO3- and K+ are reabsorbed from proximal tubule. 1-Proximal tubular reabsorption ❖ Sodium is reabsorbed by counter transport secreting H+ ions into tubular lumen. ❖ The proximal tubule is also the site for secretion of organic acids and bases (Bile salts, Oxalate, Uricacid or urate, catecholamines), drugs, toxins and para-aminohippuric acid (PAH). ❖ The average person can clear about 90 % of the PAH from the plasma flowing through the kidneys and excrete it in the urine, so PAH clearance is used to estimate the RBF and GFR 2-Solute and water transport in the Loop of Henle ❑ The loop of Henle consists of three segments: The thin descending, thin, and thick ascending. ❑ The thin descending and thin ascending segments of the loop of Henle have thin epithelial membrane with no brush borders, few mitochondria, and minimal levels of metabolic activity. 2-Solute and water transport in the Loop of Henle In descending thin segment about 20% (high permeability) of the filtered water is reabsorbed but it is moderately permeable to urea and Na+. The ascending limb, including both the thin and the thick portions, is impermeable to water. 2-Solute and water transport in the Loop of Henle The thick segment of the loop of Henle has thick epithelial cellsthat have high metabolic activity. About 25 % of the filtered loadsof Na+, Cl-, and K+are reabsorbed in the loop of Henle, mostly inthe thick ascending limb. The thin segment of the ascending limbhas a much lower reabsorptive capacity than the thick segment. 2-Solute and water transport in the Loop of Henle In the thick ascending limb, the Na+ is reabsorbed by 1-Na+- 2 Cl-- 1K+co-transporter{by it, the energy from downhill Na+ reabsorption drive the K+ reabsorption uphill ( its action is inhibited by “loop” diuretics as furosemide)} 2-by sodium hydrogen counter-transport mechanism. ❑ There is also paracellular reabsorption ofMg++, Ca++, Na+, and K+, in the thick segment due to relative more +ve chargein lumen than interstitial fluid due to a slight back leak of K+ ions into the lumen. 3-Distal Tubule ❖ The first portion of the distal tubule is part of the Juxtaglomerular complex. ❖ The next part is the early distal tubule is highly convoluted and reabsorbs Na+, K+, and Cl-, but is impermeable to water and urea(diluting segment). ❖ About 5 % of sodium chloride isreabsorbed in the early distal tubule by Na+- Cl-co-transporter (inhibited by thiazide diuretics). ❖ Cl- diffuses from the cell into the renal interstitial fluidthrough chloride channels in the basolateral membrane. 4-Late distal tubule and cortical collecting tubule Late distal tubule and cortical collecting tubule: both have same functions which are: 1- Both have two cell types, the principal cells and the intercalated cells. ❑ Principal cells: reabsorb Na+ and secrete K+(depend on Na+-K+ ATPase pump and concentration gradient)under the effect of the aldosterone hormone.Principal cells reabsorbe water as well. ❑ Intercalated cells: secrete H+ (by hydrogenATPase) and reabsorb both HCO3 and K+ ions. 2- Almost completely impermeable to urea. 4-Late distal tubule and cortical collecting tubule 3-The permeability of both segments to water is controlled by the concentration of antidiuretic hormone ADH (vasopressin). With high levels of ADH, these tubular segments arepermeable to water, but in the absence of ADH, they arealmost impermeable to water. 5-Medullary collecting ductIt is the final site process the urine and reabsorbs less than 10 % of the filtered H2O and Na+. The epithelial cells of it are nearly cuboidal with smooth surfaces and relatively few mitochondria.The characteristics of medullary collecting duct are: 1. The permeability of it to water is controlled by the level of ADH ( ADH increases its permeability to water forming concentrated urine). 2. It is permeable to urea (important in concentrated urine). 3. It secretes H+ ions against a large concentration gradient (important in acid-base balance).  5-Medullary collecting duct Note//Principal cells; located in initial collecting tubule and the cortical and outer medullary collecting ducts, have cellular receptors to bind both aldosterone (released from the adrenal cortex) and antidiuretic hormone (released from the posterior pituitary). Intercalated cells (types A and B); the remainder of the cortical and outer medullary collecting duct cells, specialized epithelial cells that help regulate urine pH.  S 1 L1 THANK YOU