Physiology 3.01a Renal Physiology I.pdf

3.01a

November 04, 2015 Fernando P. Solidum, MD., DPBA



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TOPIC OUTLINE I. Functions of the Kidney II. Structure of the Kidney a. Layers of the Kidney b. Other Parts III. Nephron a. Parts of the Nephron b. Vasa Recta IV. Ultrafiltration V. Filtration Barrier VI. Mesangium VII. Extraglomerular Mesangial Cells VIII. Ultrastructure of the Juxtaglomerular Apparatus IX. Assessment of Renal Function a. Inulin Clearance b. Creatinine Clearance c. Filtration Fraction X. Glomerular Filtration Rate XI. Renal Blood Flow XII. Mechanisms of Autoregulation XIII. Regulation of RBF and GFR XIV. General Principles of Transepithelial Solute and Water Transport

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Minor Calyx: collects urine from each papillar Major Calyx: combination of minor calyces Pelvis: combination of major calyces; represents the upper and expanded region of the ureter Ureter: carries urine to bladder Fluids from glomerulus....................................................................ultrafiltrate Fluids in nephron segments.........................................................tubular fluid Fluids that leave the collecting ducts.......................................................urine



FUNCTIONS OF THE KIDNEY Regulates: o Body fluid osmolality and volumes ! In dehydration – compensation is producing scanty urine ! Kidney can detect change in concentration of solutes in the body o Electrolyte balance ! In the proximal tubule 67% of electrolytes are filtered and reabsorbed o Acid-base balance ! pH adjustment through pulmonary and renal mechanisms ! 3rd line of defense in acid-base balance Excretes metabolic products and foreign substances from fat and carbohydrate metabolism Produces and secretes hormones o This is the most important function o Erythropoietin which is the precursor of RBC production o Renin for RAAS activation (precursor of Angiotensin II)

Body Osmolality – 300 mOsm will be used for consistency ↑ osmolality = dehydration, ↑ ADH secretion ↓ osmolality = fluid overload, ↓ ADH secretion

STRUCTURE OF THE KIDNEY A. Layers of the Kidney 1. Cortex o Outermost layer; where glomerulus can be found 2. Medulla o Innermost layer; where most absorption takes place 3. Pelvis o Junction between kidneys and ureters B. Other parts • Renal Pyramids: conical masses in the medulla • Papilla: apex of the pyramid, its base originates at the corticomedullary border; lies within a minor calyx

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RENAL PHYSIOLOGY I



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Blood Supply: o Blood flow is equivalent to about 25% of CO (1.25L) in resting individuals o Renal Artery ! Interlobar Artery ! Arcuate Artery ! Interlobular Artery ! Afferent Arteriole ! Glomerular Capillaries ! Efferent Arteriole ! Peritubular Capillaries (2nd capillary network which supply blood to nephron)



NEPHRON Basic functional unit of the kidney Each kidney contains about 1.2 million nephrons Can reach outer medulla and others can go as far as inner medulla Have varied strength to dilute or concentrate tubular fluid Classified based on their locations: o Cortical Nephrons ! Its loop of Henle reaches the outer medulla (outer medulla ang pinakamalalim na pwede nyang maabot) ! Vascular supply: Peritubular Arteries o Juxtamedullary Nephrons ! Covers the inner medulla of the kidney and its loop of Henle runs side by side the vasa recta and deep medulla (mas malalim ang naabot ng loop of Henle nya compared kay cortical) ! Vascular Supply: Vasa Recta • Vasa Recta – receives H2O and other solutes and returns it back to circulation; dilutes/concentrates urine; countercurrent exchangers A. Parts of the Nephron 1. Renal Corpuscle • Consist of: a. Glomerulus • • • • •

3.01a

Renal Physiology I

Network of capillaries supplied by the afferent and efferent arterioles High hydrostatic pressure (60mmHg) Has three layers (will be discussed later in filtration barrier): ! Capillary Endolthelium ! Basement Membrane ! Podocytes Bowman’s Space Space between visceral and parietal layer that separates Bowman’s capsule and glomerulus. Ultrafiltrate ang tawag kapag andito pa lang ang fluid. Okay?! ☺ Bowman’s Capsule where the filtrate goes after passing the glomerulus. -

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Proximal Tubule • 67% of Na, Cl and H20 and 95% of HCO3- and proteins that enters the tubules is being handled by proximal tubule (absorption / filtration) • Presence of brush border that increases surface area for tubular reabsorption • Contains very high number of mitochondria • ISOSMOTIC and H2O PERMEABLE • Lies in the cortex of the kidney and drains into the Loop of Henle Loop of Henle • Involved in the dilution and concentration of tubular fluid • Countercurrent multiplier • NO BRUSH BORDERS • Poorly developed apical and basolateral membranes and few mitochondria • Different parts of the loop have different permeabilities and functions: o Thin descending limb Ends in hairpin turn Concentrating segment: permeable to water so it tends to lose water while solutes remain Outer to inner medulla o Thin ascending limb Permeable to water o Thick ascending limb Starting to regain mitochondria (there is active transport of NaCl and other solutes as it approaches the distal convoluted tubules) Outer medulla to cortex Macula Densa ! short segment of thick ascending limb

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Part of the Juxtaglomerular apparatus that is important in autoregulating NaCl concentration

Distal Tubule • Increased number of mitochondria • Aids in active transport of NaCl and other solutes Cortical Collecting Ducts • Initially impermeable to water • ADH changes it to permeable by morphologically activating aquaporins • Note: The 2nd half of distal convoluted tubule and the rest of the collecting ducts contain specialized that act primarily in K+, HCO3-, and H+ transport; they are: o Principal cells For Na absorption/excretion 8% in number of all specialized cells o Intercalated cells For H+ and HCO3- absorption/excretion Acid- base regulation



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Vasa Recta Forms capillary networks that surrounds the collecting ducts and the ascending limbs of Henle Conveys Oxygen to the nephron segments Supplies nutrients to nephron segments Acts as a pathway for reabsorbed water and solutes to the circulatory system Concentrates and dilutes urine

ULTRAFILTRATION •

Refers to the passive movement of an essentially protein-free fluid from the glomerular capillaries into Bowman’s space.

FILTRATION BARRIER



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Renal Physiology I

Not all of the blood that passes through the glomerulus is filtered. The structures that act as filtration barriers are: 1. Capillary Endothelium ! Fenestrated, freely permeable to water ! With negatively-charged glycoproteins on its surface ! Synthesize vasoactive substances like Nitric oxide (vasodilator), and endothelin (vasoconstrictor) ! Negatively charged solutes will not be filtered 2. Basement Membrane ! Also negatively charged proteins ! Charge selective filter ! Cationic molecules are filtered more readily than anionic molecules for molecules with an effective molecular radius between 20 and 40 3. Foot Processes of Podocytes ! Endocytic properties ! Have long, finger-like processes that completely encircle the outer surface of the capillaries ! Interdigitate to cover the gaps between the basement membrane ! Separated by gaps called filtration slits ! PODOCALYXIN Negatively charged membrane glycoprotein in podocytes Keep the filtration slits open Notes: Exceptions on the negatively charged solutes which can cross the filtration barrier 1. Small radius size 2. Hydrostatic pressure in the capillaries In cases of renal disease (example glomerulonephritis), the filtration barrier: - Inflammation causes destruction of filtration barrier - Flattening of the 3 layers - Widening of filtration slits → everything can cross - Urinalysis: presence of proteins, glucose, blood, RBC

ULTRASTRUCTURE OF THE JUXTAGLOMERULAR APPARATUS • • • • •

Important in tubuloglumerular feedback mechanism Involved In autoregulation of GFR and renal blood flow Regulate blood flow in arterioles Controls the amount of blood going to the glomerulus Has three components: 1. MACULA DENSA of the THICK ASCENDING LIMB ! Passes through the AA and EA of the same nephron ! Contacts with mesangial cells and granular cells – derived from metaphroc mesenchymal cells which manufacture, store and release renin ! Function as chemoreceptor or osmoreceptor 2. EXTRAGLOMERULAR MESANGIAL CELLS ! Mesangial cells appear to control the glomerular filtration rate 3. RENIN-PRODUCING GRANULAR CELLS of the AFFERENT ARTERIOLES ! Modified smooth muscle that store, manufacture and release renin ! Act as a mechanoreceptor ! Renin: involved in angiotensin II formation, secretion of aldosterone

MESANGIUM • • • •

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Structural support for the glomerular capillaries Maintains the roundness of the glomerulus (structural support) Possess smooth muscle properties Consists of: o Mesangial cells ! Similar to monocytes ! Surround glomerular capillaries ! Provide structural support to the glomerular capillaries o Mesangial matrix Other functions: o Secrete the extracellular matrix o Surround glomerular capillaries o Exhibit phagocytic activity by removing macrophages o Secrete prostaglandins and proinflammatory cytokines o Influence GFR via regulating blood flow through the glomerular capillaries or by altering the capillary surface area.

EXTRAGLOMERULAR MESANGIAL CELLS or LACIS CELLS or GOORMAGTIGH CELLS

Notes: If pressure in AA is ↑, more blood is filtered in glomerulus à ↑ultrafiltrate à tubular fluid Remember: MD will sense if the fluid is matabang or maalat "will send signal to EGM " EGM will send signal to AA if it will vasodilate (if matabang) or will vasoconstrict (if maalat). After vasodilation, there will be ↑GFR and ↑[NaCl]. After vasoconstriction, there will be ↓GFR and ↓[NaCl].

ASSESSMENT OF RENAL FUNCTION

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Mesangial cells outside the glomerulus Exhibits phagocytic activity

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MESANGIUM

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There are 3 general processes which determines the amount of substances that appears in the urine: 1. Glomerular filtration 2. Reabsorption of substances from tubular fluid 3. Secretion of substances from blood to tubular fluid Renal Clearance A theoretical measurement of Glomerular Filtration Rate (GFR) and Renal Blood Flow (RBF) Based on Fick principle (mass balance or conservation of mass)

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Renal Physiology I

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Inulin Clearance Used to measure GFR Inulin o Polymer of fructose o Neither reabsorbed nor metabolized o All inulin enetering the renal artery is not filtered at the glomerulus; the rest return to the renal veins (only 15-20% filtered) o Not produced by the body o Freely filtered across the glomerulus into the Bowman’s space o Amount of Inulin filtered = Amount excreted



𝑮𝑭𝑹 = Input: 𝑷𝒂𝒙 ×𝑹𝑷𝑭𝒂 Red upper blood vessel = renal artery Output: 𝑷𝒗𝒙 ×𝑹𝑷𝑭𝒗 + 𝑼𝒙 ×𝑽 Blue lower blood vessel = renal vein Yellow inferior bent vessel = renal pelvis + ureter



𝑷𝒂𝒙 ×𝑹𝑷𝑭𝒂 = 𝑷𝒗𝒙 ×𝑹𝑷𝑭𝒗 + 𝑼𝒙 ×𝑽

Where: 𝑷𝒂𝒙 = concentration of substance X in renal artery 𝑹𝑷𝑭𝒂 = renal plasma flow rates in artery 𝑷𝒗𝒙 = concentration of substance X in renal vein 𝑹𝑷𝑭𝒗 = renal plasma flow rates in veins 𝑼𝒙 = concentration of substance in urine 𝑽 = urine flow rate The equation means: The amount of substance X that enters the kidney in the renal artery is equal to the amount that leaves the kidney to the systemic circulation and urine via the renal vein and urethra respectively. However, clearance does not measure all these factors. Clearance is the volume in which all substances has been removed and excreted into urine per unit in time. • Considers only the rate at which a substance is excreted in the urine. • Also determines if a substance is reabsorbed or secreted

𝑪𝒙 =

Where: 𝑮𝑭𝑹 = Glomerular Filtration Rate 𝑼𝑰𝒏 = Urine concentration of Inulin 𝑷𝑰𝒏 = Plasma concentration of Inulin 𝑽 = Urine flow Creatinine Clearance • Can also be used to measure GFR • Creatinine o by product of skeletal muscle creatine metabolism o Thought to be produced at a constant rate o Freely filtered across the glomerulus into Bowman’s space o Amount of Creatinine filtered = Amount excreted o

𝑮𝑭𝑹 =

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𝑼𝑪𝒓 ×𝑽 𝑷𝑪𝒓

Where: 𝑮𝑭𝑹 = Glomerular Filtration Rate 𝑼𝑪𝒓 = Urine concentration of Creatinine 𝑷𝑪𝒓 = Plasma concentration of Creatinine 𝑽 = Urine flow Relationship between GFR and Creatinine

↑GFR = ↓Plasma Creatinine (because creatinine is excreted) ↓GFR = ↑Plasma Creatinine (because creatinine is retained)

𝑼𝒙 ×𝑽 𝑷𝒂𝒙

𝑪𝒙 = clearance ”For any substance that is neither synthesized nor metabolized, the amount that enters the kidneys is equal to the amount that leaves the kidneys in the urine plus the amount that leaves the kidneys in the renal venous blood.” Glomerular Filtration Rate • Sum of the filtration rates and all functioning nephrons: index of kidney functions • Fall in GFR: Kidney disease progress • Determines prognosis of disease Normal values: Males: 90 to 140 ml/min Females: 80 to 125 ml/min Factors to be considered to appropriately measure GFR 1. Substance freely filtered across glomerulus into Bowman’s space 2. Substance not be reabsorbed or secreted by the nephron 3. Substance not be metabolized or produced by the kidney 4. Substance itself does not alter GFR

𝑼𝑰𝒏 ×𝑽 𝑷𝑰𝒏

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Concerns in the use of Plasma Creatinine 1. Not accurate o Renal tubules can secrete creatinine = overestimation of GFR (kasi pwede pa ring maging part ng urine ang creatinine) 2. Creatinine production is not constant to all individuals 3. A slight increase in serum creatinine would correspond to a decrease in renal function from 100% of normal.

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Renal Physiology I

FILTRATION FRACTION Filtration Fraction = GFR/RPF Portion of the plasma that is filtered 60% of blood is plasma " will be filtered by the glomerulus 15 to 20% of plasma that enters the glomerulus is actually filtered Remaining 80 to 85% continues to pass through the glomerulus to the efferent arterioles to peritubular capillaries to the systemic circulation

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The reduced filtration rate for anionic molecules is explained by the presence of negatively charged glycoproteins on the surface of all components of the GFB (which repel similar charges)

If a substance is freely filterable in terms of size but is negatively charged, how can it cross the filtration barrier? With increased hydrostatic pressure

GLOMERULAR FILTRATION RATE Normal GFR o Males: 90-140 ml/min o Females: 80-125 ml/min o 180L/day of plasma filtered o After age 30, GFR declines but does not adversely affect the kidney’s functions

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ULTRAFILTRATE The 1st step in the formation of urine Devoid of cellular elements (i.e. red and white blood cells and platelets) and is protein free Same composition with plasma Starling forces drive ultrafiltrate across the glomerular capillaries Changes in Starling forces alter the GFR GFR (Glomerular Filtration Rate) and RPF (Renal Plasma Flow) are normally held within very narrow ranges by autoregulation.

A. Determinants of Ultrafiltrate Composition • The structure of the Glomerular Filtration Barrier determines composition of the plasma ultrafiltrate. o Capillary Endothelium o Basement Membrane o Filtration Slits (Podocytes) • GFB restricts the filtration of molecules on the basis of both SIZE and ELECTRICAL CHARGE. o Size • 20Å = Filtered freely (wee!) • 20Å - 42Å = Filtered to various degrees, depending on the charge • > 42Å = NOT FILTERED o Electrical Charge • Cations = readily filtered • Anions = restricted filtration due to the repulsion by the negatively charged proteins present on the barrier (GFB)

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B. Dynamics of Ultrafiltration • Forces responsible for glomerular filtration of plasma are the same as those in all capillary beds (Starling Forces) • Ultrafiltration occurs because the Starling forces (i.e. hydrostatic and oncotic pressure) drive fluid from the lumen of glomerular capillaries, across the filtration barrier, and into the Bowman’s space Glomerular capillaries "across GFB " Bowman’s Space A. Facilitates Filtration •



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As the size increases, filterability (ability to pass through the GFB) decreases " inverse relationship Not exceeding 42 Å, cations have greater filterability than anions.

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Reduction of the negative charges on the glomerular wall (GFB) causes proteins to be filtered solely on the basis of their effective molecular radius.

Glomerular Capillary Hydrostatic Pressure (PGC) o Promotes the movement of fluid from the glomerular capillary into the Bowman’s space o Decreases slightly along the length of the capillary because of the resistance to flow along the length of the capillary o Only force that favors filtration o Increased when there is increased blood flow in afferent arterioles o Decreased when afferent arteriole is constricted Oncotic Pressure in the Bowman’s Space (πBS) o Increases oncotic pressure in the Bowman’s space can facilitate filtration, but since the glomerular ultrafiltrate is protein-free, and the oncotic pressure in the Bowman’s space is near zero therefore, GC Hydrostatic Pressure is the only force that favors filtration. o Only in abnormal states where πBS is increased that it can contribute to filtration

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Changes in afferent arteriolar resistance a) ↓ resistance→ ↑ PGC → ↑ GFR b) ↑ resistance→↓ PGC → ↓ GFR Changes in efferent arteriolar resistance a) ↓ resistance →↓ PGC → ↓ GFR b) ↑ resistance →↑ PGC → ↑ GFR Changes in renal arteriolar resistance a) ↑ BP→ ↑ PGC → ↑ GFR b) ↓ BP→↓ PGC → ↓ GFR

RENAL BLOOD FLOW (RBF) At rest: 25% of CO (1.25L/min) Functions: 1. Indirectly determines the GFR 2. Modifies the rate of solute and water reabsorption by the proximal tubule 3. Participates in the concentration and dilution of urine 4. Delivers O2, nutrients, and hormones to the cells of the nephron and returns CO2 and reabsorbed fluid and solutes to the general circulation 5. Delivers substrates for excretion in urine • Blood flow through any organ may be represented by the equation: Q = ∆P/R Q = blood flow, ∆P = mean arterial pressure minus venous pressure for that organ, R = resistance to flow through that organ. • Accordingly, RBF is equal to the pressure difference between the renal artery and the renal vein divided by renal vascular resistance. • •

B. Opposes Filtration •

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Hydrostatic Pressure in the Bowman’s Space (PBS) o If this force is greater than the hydrostatic pressure in the GC, it prevents filtration as it exerts greater force on the GFB in relation to the force that PGC exerts " happens where there is an obstruction somewhere along the tubules Oncotic Pressure in the Glomerular Capillary (πGC) o Increases along the length of the glomerular capillary, because water is filtered and protein is retained in the glomerular capillary, so the protein concentration in the capillary rises, and πGC increases

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The afferent arteriole, efferent arteriole, and interlobular artery are the major resistance vessels in the kidneys and thereby determine the renal vascular resistance.

Net Ultrafiltration pressure (PUF): o o o

Afferent end of glomerulus: 17 mmHg Efferent end of glomerulus: 8 mmHg PUF = PGC – PBS – πGC

C. GFR Alteration • GFR is proportional to the sum of the Starling Forces that exist across the capillaries multiplied by the ultrafiltration coefficient (Kf) so that any change in the Starling forces changes GFR GFR= Kf [(PGC - PBS) - σ(πGC - πBS)] * The reflection coefficient for protein across the glomerular capillary (σ) = 1 • Kf is the product of the intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration • As Kf increases, GFR increases. • GFR can be altered by changing Kf or by changing any of the Starling forces. From the equation above: o Changes in Kf: ↑ Kf → ↑ GFR o Changes in PGC: ↑ PGC → ↑ GFR o Changes in PBS: ↑ PBS→ ↓ GFR o Changes in πGC: ↑ πGC → ↓ GFR o πBS ~ 0 • In normal individuals, the GFR is regulated mainly by changes in afferent or efferent arteriolar resistance (which alters hydrostatic pressure in the glomerular capillaries, PGC) Changes in glomerular arteriolar resistance "alteration in PGC " GFR Regulated •

PGC is affected in three ways:

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Like most other organs, the kidneys regulate blood flow by adjusting vascular resistance in response to changes in arterial pressure. These adjustments are so precise that blood flow remains relatively constant between 90 and 180 mmHg. Relatively constant maintenance of RBF and GFR is achieved by adjusting the vascular resistance, specifically the afferent arterioles (AUTOREGULATION).

MECHANISMS OF AUTOREGULATION • •

Autoregulation is absent below 90 mmHg Autoregulation of RBF and GFR changes slightly as arterial blood pressure varies. It is not perfect, just like us.

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Renal Physiology I

GFR and RBF can be influenced by certain hormones, and by changes in sympathetic nerve activity If a significant amount of blood is lost, GFR and RBF decrease. Two mechanisms are responsible for autoregulation of RBF and GFR by regulating the tone of the afferent arteriole.

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the macula densa cells " ↓ ATP and adenosine production and

• I. Myogenic Mechanism • Pressure-sensitive mechanism • Related to intrinsic property of vascular smooth muscle: the tendency to contract when stretched

In contrast, when GFR and NaCl concentration ↓"less NaCl enters

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release " vasodilation of afferent arterioles " normalize GFR and RBF The macula densa may release both vasoconstrictors and vasodilators that oppose each other’s action at the level of the afferent arteriole. Effector substances produced by macula densa cells: o Adenosine = Vasoconstriction o Nitric Oxide (NO) = Vasodilation o Angiotensin II = Vasoconstriction

REGULATION OF RBF AND GFR Major Hormones That Influence the GFR and RBF

II. Tubuloglomerular Feedback

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How changes in afferent and efferent arteriolar resistance, mediated by changes in these hormones modulate GFR and RBF:

NaCl concentration-dependent mechanism



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At the cellular level: When GFR ↑ " NaCl concentration in the tubular fluid at the macula densa ↑ " more NaCl enters the macula densa cells" ↑ formation and release of ATP and Adenosine" ATP binds to receptos on extraglomerular mesangial cells" release vasoconstriction of afferent arteriole " normalize GFR and RBF

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II. Hormonal Control of RBF and GFR A. Angiotensin II • Through RAAS it is produced. • Constricts both afferent and efferent arterioles but efferent arterioles are more sensitive to A-II. • ↓ RBF and GFR • Angiotensin Converting Enzyme (ACE) converts Angiotensin I to II. It degrade and inactivate bradykinin

Changes in RBF •

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Constriction of either the afferent or efferent arteriole increase resistance, and according to equation Q = ∆P/R, if resistance (R) increases ↑, flow (Q) decreases ↓ Dilation of either arteriole increases flow (i.e. ↑ RBF)

Changes in GFR (A) Constriction of afferent arteriole(↓ PGC) • Because less of the arterial pressure is transmitted to the glomerulus thereby causing ↓ GFR. (B) Constriction of efferent arteriole • In contrast, constriction of the efferent arteriole elevates PGC or the hydrostatic pressure inside the glomerular capillary and thus ↑ GFR. (C) Dilation of efferent arteriole • ↓ PGC and thus ↓ GFR (D) Dilation of afferent arteriole • ↑ PGC because more of the arterial pressure is transmitted to the glomerulus, thereby increasing ↑GFR I. Sympathetic control of Renal Blood Flow (RBF) • The afferent and efferent arterioles are innervated by sympathetic neurons; however, sympathetic tone is minimal when the volume of extracellular fluid is normal • Sympathetic nerves release norepinephrine and dopamine, and circulating epinephrine is secreted by the adrenal medulla • Dehydration or strong emotional stimuli (such as fear and pain) activate sympathetic nerves, release vasoconstrictors and reduce GFR and RBF • Low blood volume and blood pressure (haemorrhage) also stimulates release of NE and Epi via baroreceptor reflex, leading to decrease in GFR and RBF

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The figure shows how norepinephrine, epinephrine, and angiotensin II act together to decrease RBF and GFR and thereby increase BP and extracellular fluid volume, as would occur with haemorrhage. B. Prostaglandin • No effect on RBF and GFR in healthy individuals • In pathological states, PGI1 and PGE2 are produced locally in the kidneys. It ↑ RBF without changing GFR. • ↑ RBF by dampening the vasoconstrictor effects of sympathetic and A-II • Prevents severe vasoconstriction and renal ischemia C. Nitric Oxide • Endothelium-derived relaxing factor • Counteracts effects of A-II and catecholamines • Dilation of afferent and efferent arterioles • It decreases TPR and inhibited production of NO ↑ BP D. Endothelin • Secreted by endothelial cells of renal vessels, mesangial cells, and distal tubular cells in response to A-II, bradykinin, Epi and stretch • Profound Vasoconstriction of afferent and efferent arterioles " ↓ RBF and GFR

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E. Bradykinin • By-product of kininogen breakdown • Kallikrein cleaves kininogen "bradykinin " stimulates release of NO and prostaglandins "vasodilation" ↑RBF F. Adenosine • Vasoconstriction of afferent and efferent arteriole • ↓ RBF and GFR • Tubuloglomerular feedback regulation G. Atrial Natriuretic Peptide (ANP) • Vasodilation of afferent arteriole • Vasoconstrictor of efferent arteriole • Modest ↑ in GFR, no change in RBF • ANP secretion increases with hypertension and expansion of extracellular fluid volume.

Transcellular Pathway • Traversing both the apical and basolateral membranes • Via (1) Passive or Facilitated Diffusion, (2) Active Transport, (3) Solvent Drag • Na+,K+-ATPase (active transport) is found in the basolateral membrane on almost all segments. o In the thick ascending limb, it is important in changing the osmolarity of the medullary interstitium. • Any solute that is actively transported across an epithelium must be transported via the transcellular pathway.

H. ATP • Dual effects on GFR and RBF • Constricts afferent arteriole and reduces RBF and GFR • May stimulate NO production and increase RBF and GFR I. Glucocorticoids • Increases GFR and RBF J. Histamine • Increases RBF without elevating GFR by decreasing resistance of afferent and efferent arterioles. K. Dopamine • Produced by proximal tubule and it increases RBF and inhibiting renin secretion This figure shows examples of the interactions of endothelial cells with smooth muscle and mesangial cells.

GENERAL PRINCIPLES OF TRANSEPITHELIAL SOLUTE AND WATER TRANSPORT Paracellular Pathway • Via tight junctions in between cells o Proximal tubule and descending limb: “loose” tight junctions o Thick ascending limb: “tight” tight junctions (practically impermeable to H2O) • Passive in nature (driving force: concentration or voltage gradient) • Tight junctions in epithelia with high transepithelial transport have very high permeability.

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PROXIMAL TUBULE Reabsorbs 67% of filtered water, Na+, Cl-, K+ and other solutes Due to the presence of the brush border (↑ surface area) and abundance of mitochondria (↑ energy) Key element in reabsorption: Na+,K+-ATPase in the basolateral membrane

SODIUM REABSORPTION FIRST HALF OF THE PROXIMAL TUBULE • Na+ is reabsorbed with bicarbonate (HCO3-) and a number of other solutes (e.g. glucose, amino acids, Pi, lactate) Mechanisms: (1) Na-H antiporter • Found in the apical membrane • Na+ reabsorbed, H+ excreted • CO2 + H20 combines to form carbonic acid(H2CO3) → acted upon by carbonic anhydrase → splits up into H+ and HCO3- → H+ goes to tubular fluid, HCO3- to the circulation • Na+ goes to the circulation via Na+,K+-ATPase • Absorbed: Na+ and HCO3- • Excreted: H+

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(2) Na-glucose symporter • • • •

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Na+ is coupled with glucose in the apical membrane Na+ goes to the circulation via Na+,K+-ATPase Glucose goes to the circulation via passive transport mechanism (GLUT2) Reabsorption of many organic molecules is so avid that they are almost completely removed from the tubular fluid in the first half of the proximal tubule. Absorbed: Na+ and glucose

SECOND HALF OF THE PROXIMAL TUBULE • Na+ is reabsorbed with Cl- via transcellular and paracellular pathways Mechanisms: (1) Transcellular pathway • 2/3 of NaCl is reabsorbed through this process • Na-H antiporter and one or more Cl-anion antiporter • H+ secreted by Na-H antiporter combines with the anion secreted by Cl-anion antiporter and reenters the cell • Na+ goes to the circulation via Na+,K+-ATPase • Cl- goes to the circulation via a K+-Cl- symporter in the basolateral membrane

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(2) Paracellular Pathway • 1/3 of NaCl is reabsorbed through this process • Happens because of the rise of [Cl-] in the tubular fluid that creates a [Cl-] gradient • Happens stimultaneously with the transcellular pathway • Movement is isosmotic (equal movement of Na and water) SOLUTE CONCENTRATION IN TUBULAR FLUID AS A FUNCTION OF LENGTH ALONG THE PROXIMAL TUBULE •

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In the first half of the proximal tubule, certain substances have already been absorbed completely such as amino acids, glucose and bicarbonate. Farther down the proximal tubule, there is still active reabsorption of Na+ and Cl-. Certain substances are easily reabsorbed compared to others

3.01a • • •

WATER REABSORPTION Driving force: transtubular osmotic gradient established by solute reabsorption Apical and basolateral membranes of proximal tubular cells express aquaporin water channels. SOLVENT DRAG: important consequence of osmotic water flow " some solutes, especially K+ and Ca++, are entrained in the reabsorbed fluid and reabsorbed by the process of solvent drag ↑Na and other solute reabsorption into the lateral intercellular space (through apical membrane) ↓ ↓Fluid osmolality of the tubular fluid ↑Fluid osmolality of the lateral intercellular space (in relation to the tubular fluid) ↓ Water flows by osmosis across the tight junctions and proximal tubule cells (to the intercellular space) ↓ ↑ hydrostatic pressure in the lateral intercellular space ↓ Fluids move into the capillaries ↓ Water is reabsorbed

REMEMBER! Proximal tubule reabsorption is ISOSMOTIC " osmolarity does not change How will osmolality decrease? Tubules should exhibit impermeability to water, as in the case of the thick ascending limb, early distal tubule, late distal tubule (unless acted upon by ADH) and collecting duct (unless acted upon by ADH). PROTEIN REABSORPTION • Protein: almost 100% reabsorption • Urinalysis: should be negative for protein • Enzyme is easily saturated o ↑↑ protein diet → saturates enzyme →proteinuria - protein is found in urine (normal) o Disruption of glomerular filtration to protein → ↑filtered protein → proteinuria Partial enzyme degradation of protein in the surface of proximal tubule cells ↓ Endocytosis ↓ Further intracellular breakdown of proteins into amino acids ↓

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Renal Physiology I

Amino acid leaves the cell via the basolateral membrane ↓ Enters capillary circulation ORGANIC CATION AND ANION SECRETION • End products of metabolisms and exogenous organic compounds, including numerous drugs and toxic chemicals, circulating in plasma o Many are not readily filtered so they are secreted from the peritubular capillaries. 1. Organic Anion Secretion: p-aminohippuric transport • Basolateral membrane: elimination from the circulation in exchange of an alpha-ketoglutarate • Apical membrane: secreted to tubular fluid in exchange of an anion PAH enters the cell via the basolateral membrane in exchange for αKG (antiport) coming from the metabolism of glutamate in the cell ↓ αKG then reenters the cell in symport with Na+ ↓ αKG recycles in the basolateral membrane ↓ ↑PAH drives the movement towards the apical membrane ↓ ↑PAH moves toward via the PAH-Anion antiporter ↓ PAH in the TF 2. Organic Cation Secretion • Organic cation is secreted in exchange of one H+ • One mechanism by which H+ is brought back into the cell (recall that H+ is secreted via the Na-H antiport)

3.01a

Renal Physiology I

LOOP OF HENLE

• • • • • • •

Important in the concentration and dilution of urine Important in the countercurrent mechanism Reabsorbs approx. 25% of filtered Na+ and K+ Key element in reabsorption: Na+-K+ ATPase → ↑ osmolarity of medullary interstitium in the thick ascending limb NaCl reabsorption: only in thin ascending and thick ascending limbs H2O reabsorption: only in descending thin limb Thick ascending limb: o 1Na+-1K+-2Cl- symporter: (in the apical membrane) mediates Na+ movement across the cell o Na-H exchanger o Tight junctions: Na+, K+, Ca++, Mg++ (but not H2O " decreases the osmolarity of the tubular fluid) o “diluting segment” – increased reabsorption

Mechanisms: (1) Transcellular Pathway 1Na+-1K+-2Cl- symporter

Intracellular Na+ (via Na+,K+-ATPase) < TF ↓ Na+ moves together with K+ and 2 Cl- across the apical membrane (AM) via 1Na+-1K+-2Cl- symporter (downhill movement of Na+ and Cl- releases potential energy which drives K+ uphill inside the cell) ↓ Na+ leaves the cell at BLM via Na+,K+-ATPase ↓ K+ and Cl- leave the cell by separate pathways Na-H Antiporter Na entry to the apical membrane is coupled with pumping out of H+ via Na-H antiporter ↓ H+ secretion results in NaHCO3 reabsorption (explained earlier as to why) ↓ Na+ leaves the cell at BLM via Na+,K+-ATPase ↓ HCO3- leaves the cell by diffusion (2) Paracellullar Pathway • Voltage across the thick ascending limb is important in the reabsorption of several cations such as Na+, K+, Ca2+ and Mg2+ via the paracellular pathway.

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↑salt transport → ↑ positive charge of the lumen ↓ TF is positively charged compared to blood ↓ Na+, K+, Ca2+ and Mg2+ in the TF will move to the more negative side (blood) via electrical gradient at the tight junctions ↓ ↓ osmolality of TF to 150mOsm/kgH2O (water is not reabsorbed at the thick ascending limb) DISTAL TUBULE AND THE COLLECTING DUCT Reabsorbs approximately 7% of filtered NaCl Water reabsorption depend on ADH levels Na+, Cl- and Ca2+ reabsorbed in the early segments Impermeable to water

• • • • LATE DISTAL TUBULES AND COLLECTING DUCT: Cell Types: 1. Principal Cells – reabsorb Na+ and water and secrete K+; Na+,K+ATPase 2. Intercalated Cells – secrete H+ or HCO3- and regulate acid-base balance; ATP-driven H+ pump

3.01a

Renal Physiology I



SUMMARY NACL TRANSPORT ALONG THE NEPHRON Percentage Mechanism of Na+ transport Filtered across the AM Reabsorbed Proximal tubule 67% Na+H+ exchange Na+-contransport with glucose, amino acids and other organic solutes Na+H+Cl-Anion exchange Loop of Henle 25% 1Na+1K+2Cl- symport Early Distal ~4% NaCl symport Tubule Late DT and ~3% Na+ channels Collecting Duct WATER REABSORPTION ALONG THE NEPHRON Segment Percentage Mechanism of water Filtered absorption Reabsorbed Proximal tubule 67% Passive Loop of Henle 15% DTL only, passive Early Distal 0% No water reabsorption Tubule Late DT and ~8-17% Passive. Collecting Duct ADH must be present. Segment

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13 of 13 Renal Physiology I [Witty trans group name]