1、 Urine Formation by the Kidneys教學方式：講授、討論、自學自學內(nèi)容：腎臟功能概述 腎小球濾過過程 腎小管重吸收和分泌功能 排尿反射腎臟生理教學安排主要參考資料：1.姚泰主編，人體生理學（上、下冊）第3版， 人民衛(wèi)生出版社 20012.鄭煜主編，生理學，第1版，高等教育出版社 20103.朱大年主編，生理學，第8版，人民衛(wèi)生出版社 20134.Robert M.Berne. Physiology. 12th ed， 北京醫(yī)科大學出版社 20135.Guyton AC, Hall JE. Textbook of Medical Physiology. 12th ed,

2、 Saunders 2011 網(wǎng)站：/G2S/Template/View.aspx?courseId=43&topMenuId=118273&action=view&type=&name=&menuType=1/wiki/Human_Physiology 復 習 題何謂排泄、腎小球濾過率、濾過分數(shù)、腎清除率？2. 簡述原尿生成的過程和影響原尿生成因素。3. 在動物實驗中，靜脈輸入大量生理鹽水或輸入 20%葡萄糖溶液20ml，尿量有何變化？為什么？4. 簡述腎素的來源及其在尿生成調(diào)節(jié)中的作用。5. 試述醛固酮在尿生成中的作用及其分泌調(diào)節(jié)。6. 試述血管升壓素對尿生成的作用及其分泌調(diào)節(jié)。7. 試分

3、析水利尿和滲透性利尿有何區(qū)別？ 思考討論題1. 試分析腎臟在維持內(nèi)環(huán)境穩(wěn)態(tài)中的作用。2. 當尿量明顯減少或增多時對內(nèi)環(huán)境穩(wěn)態(tài)有何影響？ 3. 根據(jù)尿生成的原理，討論利尿劑可通過哪些途徑 使尿量增多？4. 急性大失血時尿量有何變化？為什么？5. 當尿量增多或減少時，如何分析引起尿量變化的 原因？6. 試分析腎功能衰竭時，對尿生成有何影響？ 對內(nèi)環(huán)境穩(wěn)態(tài)有何影響？7. 試比較靜脈大量輸入生理鹽水，靜脈輸入少量20% 葡萄糖溶液和大量喝清水引起尿量增加的機制。 How is metabolic waste products excreted? How do the body maintain the

4、 homeostasis of the internal environment?Nephrotic Syndrome（腎病綜合癥）Glomerulonephritis（腎小球腎炎）Pyelonephritis（腎盂腎炎）Renal Calculus（腎結(jié)石）Renal Failure（腎功能衰竭）Kidney Transplantation（腎移植）Question: Section 1 Introduction of Kidney Concept of excretion Pathways for excretion Functions of the kidneys Functional

5、anatomy of the kidneys Research methods of the kidney functions Topics in the Section Definition and the Pathways for Excretion Definition of Excretion: The most of metabolic waste products, foreign substances, excessive water and solutes are excreted by some excreting ways.Metabolic waste products:

6、 urea, creatinine, uric acidForeign substances: drugs, food additives, toxinsExcessive electrolytes: Na+, K+, Cl-, H+, Ca2+ respiratory organ gastrointestinal tract skin kidney The pathways for excretion11 II. Functions of the kidneys excrete metabolic waste products and foreign chemicals maintain t

7、he balance of water, electrolyte, pH and osmotic pressure of the internal environment12 Functions of the kidneys secret hormone renin（腎素，球旁細胞分泌） erythropoietin (EPO) （促紅細胞生成素, 腎皮質(zhì)間質(zhì)細胞分泌） kinins （激肽，近端小管、遠端小管細胞分泌） prostaglandins (PG) （前列腺素，腎髓質(zhì)間質(zhì)細胞分泌） filtrationprimary urinereabsorptionsecretionexcret

8、ion urineProcess of urine formation: Filtration in glomerulus Reabsorption in renal tubule and collecting duct Secretion in renal tubule and collecting duct Functional Anatomy of the KidneysCollecting ductProximaltubuledistal tubuleloopof HenleRenal corpuscleglomerulus 1. Nephron the functional unit

9、e of the kidneysScanning Electron Micrograph of Renal Capsule Juxtaglomerular cell: Ruyter, 1925 secrete renin Macula densa: receptor sense the changes of flow volume sense the concentration of NaCl in renal tubular fluid regulate renin secretion Mesangial cell: produce phagocytic activity 2. Juxtag

10、lomerular ApparatusJuxtaglo-merular cellmacula densamesangial cellafferent Aefferent Athe distal tubuleJuxtaglomerular ApparatusJuxtaglomerular Apparatus3. Characteristics of Renal Blood Circulation RBF: 1200 ml/min, 1/4 CO the glomerular capillary bed high hydrostatic pressure bed the peritubular c

11、apillary bed low hydrostatic pressure bed high plasma colloid osmotic pressure bed 4. Innervation of the Kidneys1) Efferent Fibers of the Kidneys Renal sympathetic nerve: regulation of RBF, renin secretion, reabsorption of Na+, Cl- Neurotransmitter: NE, DA2) Afferent Fibers of the Kidneys Part 2 Res

12、earch Methods of the Kidney Functions Renal Clearance 1. Renal clearance the volume of plasma per unit of time that the substance is completely cleared by the kidneys C = 125 ml/minC = U . VP( ml/min ) 2. Determination of GFR Inulin Endogenous creatinine Richard 1935, Inlulin, MW 5200 Glomerular fil

13、tration rate (GFR): the amount of fluid that passes from the glomerulus into Bowmans capsule per unit of time Determination of GFR InulinCin =Uin Pin V GFR = 93159 ml/min . 1.73m2= GFRF (GFR) =UV P= CU V = PF (GFR)- R + S 3. Determination of RPF and RBF Para-aminohippuric acid, PAH RPF =U . V P= CPA

14、HRPF = CPAH / EPAH（腎動脈血漿PAH提取率） (effective renal plasma flow)RBF = CPAH / EPAH ( 1-Hematocrit )UPAH V = RPF PPAH 5. Free-water clearance, CH2O 4. Determination of renal tubule function by the clearance Cx Cin , X net secretion in the tubules Solute-free waterFree-water reabsorptionCosm = PosmV CH2O

15、= V - Cosm=V( 1 -UosmPosm)UosmCinCx/Cin1Cx/Cin1 Micropuncture and Microperfusion1）Micropuncture2）Microperfusion Intracellular Microelectrode Record Patch Clamp Molecular Biological TechniqueMicropuncture: Brenner, 1940sFig Micropuncture and Microperfusion filtrationprimary urinereabsorptionsecretion

16、excretion urineProcess of urine formation: Filtration in glomerulus Reabsorption in renal tubule and collecting duct Secretion in renal tubule and collecting duct Section 2 Glomerular Filtration Definition of glomerular filtration Characteristics of glomerular filtration membrane Effective filtratio

17、n pressure Glomerular filtration rate Filtration fraction Factors affecting GFR Topics in the Section Pate 1 Glomerular Filtration Glomerular Filtration: When blood flows through glomerular capillary, the part of plasma (except plasma proteins) is filtered into Bowmanscapsule to form primary urine (

18、initial urine). ultrafiltration ultrafiltrate (primary urine)DefinitionMicropuncture Plasma Primary Urine Urine (g/L)Water 900 980 960Na+ 3. 30 3. 30 3. 50K+ 0. 20 0. 20 1. 50Cl- 3. 70 3. 70 6. 00HPO4-/H2PO4- 0. 04 0. 04 1. 50Glucose 1. 00 1. 00 Creatinine 0. 01 0. 01 1. 00Urea 0. 30 0. 30 18. 00Uri

19、c Acid 0. 04 0. 04 0. 50Protein 70-90 0. 30 Tab The components of Plasma, Primary Urine and Urine Glomerular Filtration Membrane and its Permeability Glomerular Filtration: protein-free and devoid of cellular elements selective filtration base on molecular size and electrical chargeStructure: Endoth

20、elial Cell of Capillary Basement Membrane Epithelial Cell (Podocyte) epithelial cell (podocyte)basement membraneendothelial cell of capillaryepithelial cellfiltration slit 4-11nmbacement membranemeshwork 2-8nmendothelial cellof capillaryfenestration 70-90nmFig The structure of filtration membraneCol

21、lagen , Laminin, Agrin, Fibronectin, Nephrin /cg.1/165/F3 Fig The glomerular filtration barrier /cmecon.446.htmlMarilyn G. Farquhar. The glomerular basement membrane: not gone, just forgotten. J. Clin. Invest. 2006; 116(8): 2090-2093 Characteristics of glomerular filtration membrane mechanical barri

22、er electrical barrierwaterpositive ionglucosenegativeion白蛋白protein Dynamics of Glomerular Filtration1. Effective Filtration Pressure _ force of the filtrationEFP = ( PGC + BS ) - ( PBS + GC ) = PGC - PBS - GCPGC: pressure in glomerular capillaries 45PBS: pressure in Bowmans capsule 10GC: colloid osm

23、otic pressure in plasma 25-35BS: colloid osmotic pressure in Bowmans 0 capsuleEFPA = 10mmHg EFPE = 0mmHg EFP = （PC + if） - （Pif + P）AVPCPifif+32mmHg+14mmHg-25mmHg-25mmHg-2mmHg-2mmHg+8mmHg+2mmHgLymphaticCapillaryPEFP+13mmHg-5mmHgBlood CapillaryEFPA = 13 mmHg EFPV = -5 mmHg Formation and Return of Int

24、erstitial FluidFig Effective Filtration Pressure(25-35mmHg)Filtration EquilibriumPBSPGCGCEFPA = 10mmHg EFPE = 0mmHg 1. Glomerular Filtration Rate (GFR) the volume of fluid that passes from the glomerulus into Bowmans capsule by two kidneys per unit of timeSNGFR125 ml/min . 1.73m2, 180 L/dayfiltratio

25、n coefficient, EFP Glomerular Filtration Rate and Filtration Fraction Glomerular filtration rate Renal plasma flow = 125 / 660 = 19%FF = 2. Filtration Fraction (FF) the fraction of the renal plasma flow that becomes glomerular filtrate the ratio of GFR to renal plasma flow Part 2 Factors Influencing

26、 Glomerular FiltrationGFR = Kf ( PGC + BS ) - ( PBS + GC ) 1. Pressure in Glomerular CapillariesWhen the perfusion pressure in renal arteria changes between 80 and 160 mmHg, RBF remains relatively constant, PGC and GFRremain relatively constant. RBFGFRRBF(ml/min.g)Characteristics of RBF:Auto-regulat

27、ionA-BP:80-160 mmHgPressure in glomerular capillaries BP PGC EFP GFR UrineBleedingBP：40-50 mmHg Lithiasis (ureteral stones) Urinary bladder tumor obstruction of pathway for urine excretion PBS EFP GFR Urine2. Pressure in Bowmans Capsule 3. Plasma Colloid Osmotic Pressure, GCPlasma protein concentrat

28、ion Transfusion of physiological saline GC EFP GFR UrinePlasma protein generation: innutritionPlasma protein excretion: proteinuria4. Renal Plasma Flow ( QA )Fig Effect of renal plasmaflow on GFRPressure Length of glomerular capillaries filtration equilibrium Renal plasma flow ( QA ) the glomerular

29、colloid osmotic pressure rise more slowly, influence glomerular filtration equilibrium GFR Urinefiltration equilibriumPBSPGCGC6. The Filtration Coefficient (Kf)Kf: Effective permeability coefficient of filtration membrane (k) Area of filtration membrane (s) (1. 5m2)5. Rafferent A and Refferent ARA P

30、GC EFP SNGFRRE PGC EFP SNGFR Permeablity of the filtration membrane Nephrotic syndrome Electrochemical barrier Pglomerulus Proteinuria（蛋白尿） Glomerulonephritis Hematuria（血尿） Acute glomerulonephritis A filtration membrane GFR Urine （Hypouria, 少尿） Area of the filtration membrane Part 3 Regulation of th

31、e Glomerular FiltrationI Autoregulation of Renal Blood Flow (RBF) and GFR1. Autoregulation of Renal Blood FlowCharacteristics: When the perfusion pressure in renal arteria changes between 80 and 160 mmHg, RBF remains relatively constant, PGC and GFRremain relatively constant. RBFGFRRenal BloodFlow (

32、ml/min)Significance： to prevent violent change of RBF and GFRto fit the glomerular filtrationto fit the urine formationMechanism:MyogenicMechanism, TGF 2. Tubuloglomerular Feedback (TGF) in Autoregulation of GFR Schnermann, 1970 Receptor: macula densa Mechanism: Contraction of afferent A and efferen

33、t A Local renin-angiotensin system PG, NO, adenosine Fig. Micropuncture and Microperfusion Tubuloglomerular FeedbackJuxtaglo-merular cellmacula densamesangial cellafferent Aefferent Athe distal tubleGlomerular PressureSNGFRMacula Densa NaClReninAng-Efferent A ResistanceAfferent A Resistance local re

34、nin-angiotensin systemcontraction of efferent Acontraction of afferent A Fluorescence microscopic image (A) and schematic (B) of the juxtaglomerular apparatus (juxtaglomerular apparatus). Peti-Peterdi J , Harris R C JASN 2010;21:1093-10962010 by American Society of Nephrology Ca = Renin release cAMP

35、 = renin releaseNO GC, cGMP Ca2+ inhttp:/www.charite.de/ccr/site/h.neu.html /30/mede.d%3D1899 Tubuloglomerular Feedback Regulation | MedEdPORTAL Nervous and Humoral Regulation in the glomerular filtration Characteristics for nervous and humoral regulation: RBF is suitable for the systemic blood circ

36、ulation.RBF is suitable for the systemic blood circulation. Renal Sympathetic NerveTransmitter: NE1. Nervous RegulationRenal Nervous Reflex Cardiopulmonary receptor reflex Baroreceptor reflexEffects:Regulate RBF, GFR QA RBF ,GFRBleeding2. Humoral Regulation Ang Vasoconstriction effect RBF GFR Local

37、renin-angiotensin system NO, Endothelin, Bradykinin, Prostaglandins Atrial Natriuretic Peptide (ANP) GFR Section 3 Transport in Renal Tubule and Collecting Duct Concepts of reabsorption and secretion Characteristics of reabsorption Methods and pathways of transport in the renal tubule and collecting

38、 ductTopics in the SectionPrimary urine: 180 L/dayUrine: 1000ml - 2000 ml /dayPart 1 Introduction1. Definition Reabsorption:Some substances in the renal tubules are selectively reabsorbed from thetubules back into the blood. Secretion: Some substances are secreted from the blood into the tubular lum

39、en.ReabsorptionSecretion 2.Transport Methods in Renal Tubule and Collecting Duct 1) Passive Transport Diffusion, Osmosis, Solvent Drag 2) Active Transport Secondary Active Transport Against electrochemical gradient Primary Active Transport Na+K+ATPase, H+ATPase, Ca2+ATPase Along electrochemical grad

40、ientAlong osmotic gradient Secondary Active TransportTwo or more substances connect with a symport (antiport) and aretransported togetheracross the membrane at the same (different) direction.Na+ H+ Na+XX(G, AA) Vessel Renal tubuleNa+K+ATPSymport: Na+G, AA, X Antiport: Na+ H+ Cotransportelectrogenic

41、transport, neutral transport Fig Methods of the Transport in Renal Tubuleactive transportcounter-transport (symport)peritubular capillaryrenal tubuleNa+H + Na+XX（G, AA） 3. Transport Pathways of the Substances in Renal Tubules vessel renal tubule Transcellular PathwayNa+K+ATPNa+Cl H2O Na+Cl - Paracel

42、lular Pathway renal tubule vesselepithelial cell K+ Ca2+solvent drag Large quantity of reabsorption Selective reabsorption Different reabsorption rates and quantity Different methods and pathways Limitative reabsorption 4. Characteristics of the Reabsorption Primary urine: 180L /dayUrine: 1000ml-200

43、0ml /day Plasma Primary Urine Urine (g/L)Water 900 980 960Na+ 3. 30 3. 30 3. 50K+ 0. 20 0. 20 1. 50Cl- 3. 70 3. 70 6. 00HPO4-/H2PO4- 0. 04 0. 04 1. 50Glucose 1. 00 1. 00 Creatinine 0. 01 0. 01 1. 00Urea 0. 30 0. 30 18. 00Uric Acid 0. 04 0. 04 0. 50Protein 70-90 0. 30 Tab The components of Plasma, Pr

44、imary Urine and Urine Na+H+ Na+XX（G, AA） Vessel Renal tubulewaterNa+K+ATPSymport:Na+ G, AA, XNa+: primary active transportG, AA: secondary active transportAntiport: Na+-H+ exchangeH2O: osmotic reabsorption In the first half of proximal tubuleH2ONa+Cl - Renal tubule vesselIn the second half of proxim

45、al tubuleH2OSolvent drag K+ , Ca2+NaCl: passive reabsorption along electrochemical gradient Principal position of reabsorption Active transport is associated with passive transport Primary active transport is associated with secondary active transport NaCl reabsorption in thick ascending loop of Hen

46、le is associated with establishment of the medullary vertical osmotic gradient Proximal tubule 100% G (AA), 85%HCO3- 65-70% H2O, Na+, Cl-, K+, Ca2+Fig Reabsorption of the substances in renal tubuleReabsorption in Proximal Tubule 65-70% Na+, Cl-, K+, Ca2+, H2O 85%HCO3-, 100% G (AA) cotransport (sympo

47、rt, antiport) transcellular pathway paracellular pathway iso-osmotic reabsorption the principal position of reabsorptionNa+ H+ Na+XX（G, AA） Vessel Renal tubulewaterNa+K+ATPSymport:Na+ G, AA, XNa+: primary active transportG, AA: secondary active transportIn the first half of proximal tubuleH2OWater c

48、hannel (aquaporin, AQP): 11 types AQP1, AQP2, AQP3, AQP4, AQP7, AQP8，28kDAntiport: Na+ H+H2O: osmotic reabsorption 2003 Noble Prize In Chemistry/cmallery/150/memb/water.channels.htmEach monomer in tetramer aquaporinPerter AgreCHIP-28：28kDFig Reabsorption of the solutes in proximal tubuleinulinAAGThe

49、 ratio of solutes concentration in tubular fluid to plasma Na+Cl - Renal tubule vesselparacellular pathwayIn the second half of proximal tubuleH2OSolvent drag K+ , Ca2+NaCl: passive reabsorption along electrochemical gradient Symport Na+ - K+ - 2Cl- Furosemind ( - ) Na+ lumen2Cl-K+Cl-Na+ATPK+ inters

50、titial fluid K+ Na+ Thick Ascending Limb of Henles Loop H + Na+ Thick ascending limb of loop of HenleEstablishment of the medullary vertical osmotic gradientNa+H + Na+XX Vessel Renal tubuleNa+K+ATPH2OIn the first half of proximal tubule Principal position of reabsorption Active transport is associat

51、ed with passive transport Primary active transport is associated with secondary active transport NaCl reabsorption in thick ascending loop of Henle is associated with establishment of the medullary vertical osmotic gradient Proximal tubule 100% G (AA), 85%HCO3- 65-70% H2O, Na+, Cl-, K+, Ca2+ Symport

52、 Na+ - K+ - 2Cl- Furosemind ( - ) Na+ lumen2Cl-K+Cl-Na+ATPK+ interstitial fluid K+ Na+ Thick Ascending Limb of Henles Loop H + Na+ Thick ascending limb of loop of HenleEstablishment of the medullary vertical osmotic gradient Symport: Na+-K+-2Cl- Cl-K+Na+ Fig Renal medullary vertical osmotic gradient

53、Wirtz, 1951 Characteristics of reabsorption in distal tubule and collecting duct Reabsorption of water is regulated by ADH (Vasopressin) Reabsorption of NaCl is regulated by renin-angiotensin-aldosterone system Significance: Regulate the balance of water， osmotic pressure and electrolyte 103Distal T

54、ubule and Collecting DuctNa+ K+Na+Cl -Cl-Na+K+ATPNa+ K+ATP H+ATP+ HCO3-K+CO2+H2O vesselCl -thiazideamiloride Part 2 Transport in the Renal Tubule and Collecting Duct 1. Reabsorption of Glucose and Amino Acid Method: secondary active transport Position: proximal tubuleRenal threshold for glucose: 180

55、 mg / 100ml the plasma glucose level (concentration) at which the glucose first appear in theurine Diabetes GlucosuriaMechanism: the number of Na+- G symporter Na+XX（G, AA） vessel renal tubuleNa+K+ATPSymport:Na+ G, AAFig Reabsorption of Glucose and Amino Acid in Proximal Tubule G, AAcell G, AAtubule

56、 Renal Glucosuria ( SGLT)sodium-dependent glucose transporter(SGLT)FiltrationExcretionReabsorptionRate of filtration, reabsorption and excretion of glucoseRenal glucose threshold Blood glucose concentration (mg/100ml)Tm-GFig Limitative reabsorption of glucose2. Transport of HCO3- and H+Na+H +Na+ HCO

57、3-H2CO3CO2 CO2 + H +vessel ATPK+XHCO3-ATPH +renaltubuleCarbonic Anhydrase (CA)Acetazola-mideHCO3- + H+H2OH2CO3H2O +Effects:Secret H+Reabsorpt NaHCO3CACA Reabsorption of HCO3-: CO2 85% (proximal tubule) Secretion of H+: Na+ H+ antiport H+ K+ ATPase proton-pump methods Significance: Secret H+ and reab

58、sorpt NaHCO3 Maintain acid-base balance Na+H+ exchange is competed with Na+K+ exchange in renal tubule Acidosis and HyperkalemiaFactors influencing the secretion of H+ Acid-base balance K+ concentration in the blood Blood volume QA : Na+ -H+ exchange 3. Secretion of NH3 Metabolic acidosis Metabolic

59、alkalosisSignificance: Relate H+ secretion and HCO3- reabsorption Regulate acid-base balanceAntiport: Na+-NH4+NH3 diffusion: NH3 + H+ NH4+ vesselNH4+Na+NH3NH3H +NH4+H+ 4. Reabsorption and Secretion of K+ Reabsorption of K+: 65-70% in proximal tubule 25-30% in loop of Henle Secretion of K+: along ele

60、ctrochemical gradient distal tubule and collecting duct Factors affecting the secretion of K+ flow volume in distal tubule electrical gradient Na+- K+ ATPase aldosterone, K+ intake Fig Secretion of K+ in the Distal Tubule and Collecting DuctNa+ K+Na+ K+ATPK+ vesselprincipal cell 5. Reabsorption of C