25 The Urinary System P A R T A - PowerPoint Presentation

1. 25The Urinary SystemP A R T A

2. Kidney FunctionsFiltration – over 200 liters of blood filtered daily, allowing toxins, metabolic wastes, and excess ions to leave the body in urineRegulates fluid & electrolyte balanceAssists with blood acid – base balanceGluconeogenesis during prolonged fastingProduction of renin to help regulate blood pressure and erythropoietin to stimulate RBC productionActivation of vitamin DProduces some thrombopoietin

3. Urinary System OrgansKidneys (2) Paired ureters – transport urine from the kidneys to the bladderUrinary bladder – provides a temporary storage reservoir for urineUrethra – transports urine from the bladder out of the body

4. Urinary System OrgansFigure 25.1a

5. Kidney Location and External AnatomyApproximate size 12 x 6 x 3 in centimetersApproximate weight 150 gramsThe kidneys lie in a retroperitoneal position in the superior lumbar region – generally T12 – L3 – thus some protection from ribs 11 and 12 The right kidney is lower than the left because it is crowded by the liverThe lateral surface is convex; the medial surface is concaveThe renal hilus leads to the renal sinusUreters, renal blood vessels, lymphatics, and nerves enter and exit at the hilus

6. Layers of Tissue Supporting the KidneyRenal capsule – fibrous capsule that prevents kidney infectionAdipose capsule – fatty mass that cushions the kidney and helps attach it to the body wallRenal fascia – outer layer of dense fibrous connective tissue that anchors the kidneyPLAYInterActive Physiology ®: Anatomy Review, page 4

7. Kidney Location and External AnatomyFigure 25.2a

8. Internal Anatomy (Frontal Section)Cortex – the light colored, granular superficial regionMedulla – exhibits 6 – 12 cone-shaped medullary (renal) pyramids separated by columnsEach renal pyramid has a tip called the renal papillae which is perforated by 20 or so openings of the ducts of BelliniThe medullary pyramid and its surrounding corical capsule constitute a lobe (each kidney generally has between 6 to 12 lobes) Collecting System – begins with minor calyxEach renal papillae is covered by a cup like structure known as the ostium (mouth) of the Minor Calyx ( thus for every lobe of the kidney there is a minor calyx.

9. PLAYInterActive Physiology ®: Anatomy Review, page 6Internal AnatomySeveral minor calyces join together to form a major calyx. The major calyces join together to form the renal pelvis Urine flows through the renal pelvis into a ureter From the ureter urine enters the urinary bladder

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11. Blood and Nerve SupplyApproximately one-fourth (1200 ml) of systemic cardiac output flows through the kidneys each minuteArterial flow into and venous flow out of the kidneys follow similar pathsThe nerve supply is via the renal plexus. The renal plexus consists of unmyelinated sympathetic fibers that travel with the arterial supply. The cell bodies are located in the aortic and celiac plexuses. Lymphatic supply to kidney poorly understood

12. Renal Vascular PathwayAorta renal artery Anterior and Posterior division of renal artery 5 segmental arteries (do not anastomose) Lobar arteries Interlobar arteriesArcuate arteries Interlobular arteries Afferent arterioles Glomerulus Efferent arterioles Peritubular Cap and Vasa Recta (arteriolae rectae and vena rectae) Arcuate veins (if from the vena rectae) – deliver into stellate veins then to interlobular veins if from cortical peritubular capillaries then to arcuate veins Interlobar veins renal veins Figure 25.3c

13. Internal AnatomyFigure 25.3b

14. Capillary BedsFigure 25.5a

15. Renal Arteriogram

16. Capillary Beds of the NephronEvery nephron has two capillary bedsGlomerulus Peritubular capillaries OR Vasa RectaEach glomerulus is: Fed by an afferent arteriole Drained by an efferent arteriole

17. Capillary BedsPeritubular beds are low-pressure, porous capillaries adapted for absorption that: Arise from efferent arteriolesCling to adjacent renal tubulesEmpty into the renal venous systemVasa recta – long, straight efferent arterioles of juxtamedullary nephrons

18. Capillary BedsFigure 25.5a

19. Functional Unit of the Kidney – Uriniferous tubulesFunctional Unit – least amount of anatomy to explain the entire physiology The uriniferous tubules consists of the nephron (generally referred to as the functional unit of the kidney) and a portion of the collecting ductThe nephron consists of a) the glomerulus b) Bowman’s capsule c) the proximal convoluted tubule d) the Loop of Henle e) the Distal convoluted tubule and f) the connecting tubuleThe combination of the glomerulus and Bowman’s capsule constitutes the “Renal Corpuscle” Renal corpuscle – the glomerulus and its Bowman’s capsuleGlomerular endothelium – fenestrated epithelium that allows solute-rich, virtually protein-free filtrate to pass from the blood into the glomerular capsule

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21. The NephronFigure 25.4a, b

22. The nephrons are all located in the cortical region of the kidneys – but they are at three levels in the cortex . The outer cortical nephrons, the mid-cortical nephrons and the inner cortical nephrons termed the “Juxtamedullary nephrons – approximately 15% of nephrons. The juxtamedullary nephrons have the longest loops of Henle (associated with concentrating the urine). Each kidney has approximately 1 – 1.3 million nephrons. The renal corpuscle which consists of the glomerulus and Bowman’s capsule is where the actual filtration of the blood occurs.

23. Nephron PositionsOuter corticalMid-cortical (not shown)Juxta-medullaryNotice the length of the loopsof Henle – longest in the Juxta-medullary nephrons –More concentrating of urineability

24. NephronsCortical nephrons – 85% of nephrons; located in the cortexJuxtamedullary nephrons:Are located at the cortex-medulla junctionHave loops of Henle that deeply invade the medulla Have extensive thin segmentsAre involved in the production of concentrated urine

25. Renal CorpuscleThe glomerulus is a tuft of fenestrated capillaries that allows a filtrate of the blood to enter Bowman’s capsuleBetween the capillary loops of the glomerulus are Mesangial cells (intraglomerular) and some located at the vascular pole of the renal corpuscle (extraglomerular). The intraglomerular Mesangial cells are a) phagocytic thus cleaning the filter b) contractile in that they have receptors for vasoconstrictors like angiotensin II c) help support the capillaries in regions where the visceral layer of Bowman’s capsule does not come in contact with the capillaries.The extraglomerular mesangial cells are connected by gap junctions and may serve as a communication between macula densa and granular cells.

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27. Three jobs to make urine1. Filtration – removal of substances from the blood at the filter (renal corpuscle)2. Reabsorption – returning much of the filtrate (minus most of the waste) back into the blood – reason – too much has been filtered3. Secretion – active transport of substances absolutely needed to filtered into the kidneys in areas after the filter

28. Mechanisms of Urine FormationUrine formation and adjustment of blood composition involves three major processes Glomerular filtrationTubular reabsorptionSecretionFigure 25.8

29. Filtration - Composition of the FilterThe capillary fenestra – range between 70 – 90 nm – this prevents the formed elements of the blood (except a few WBCs that can perform diapedesis) from being filtered along with any macromolecules (some of the plasma proteins) whose effective size exceeds the diameter of the fenestra (atomic mass exceeds 70,000 AMUs)The Basal Lamina (300nm thick) consists of three layers the lamina densa (has type IV collagen) in the middle surrounded by a lamina rara on each side (lamina rara has the negatively charged substance heparin sulfate). The Lamina Densa traps larger proteins > 69,000 AMU and the negatively charged Lamina rara impedes negatively charged molecules from leaving (most of the plasma proteins are negatively charged).

30. Filter Continued Anatomy of the Glomerular (Bowman’s) CapsuleBowman’s capsule is composed of two layers – the internal visceral layer that actually abuts the glomerular capillaries. This layer consists of modified, branching epithelial podocytes.Extensions of the octopus-like podocytes terminate in foot processes – primary processes and secondary processes (pedicels)Filtration slits – 20 – 40 nm width openings between the foot processes that allow filtrate to pass into the capsular space

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32. Filtration Slits are coveredThe filtration slits are covered by a 6nm thick slit diaphragm which extends between the secondary pedicelsThe slit diaphragm has circular pores that are approximately 3-5 nm in diameterAs a result of the filtration anatomy – substances smaller than 3 nm easily transverse the anatomical filter – those larger than 5 nm generally do not cross . Examples of these substances would be water, electrolytes, glucose, amino acids, small proteins, urea, uric acid, creatinine and others

33. Figure 25.7a

34. Figure 25.7b, c

35. Glomerular FiltrationPrinciples of fluid dynamics that account for tissue fluid in all capillary beds apply to the glomerulus as wellThe glomerulus is more efficient than other capillary beds because:Its filtration membrane is more permeableGlomerular blood pressure is higher It has a higher net filtration pressurePlasma proteins are not filtered and are used to maintain oncotic pressure of the blood

36. Figure 25.8

37. Net Filtration Pressure (NFP)The pressure responsible for filtrate formationNFP equals the glomerular hydrostatic pressure (HPg) minus the oncotic pressure of glomerular blood (OPg) combined with the capsular hydrostatic pressure (HPc)10 mmHg = 55 mm Hg – (30 mmHg + 15mmHg)Usual pressures in most capillaries are: 10 mmHg = (35mmHg + 1mmHg) – (26 mmHg) NFP = HPg – (OPg + HPc)

38. Figure 19.16

39. Figure 25.9

40. Comparison of NFPNFP = pressure out of capillary – pressure intoForces out = MAP at capillary + Interstitial Fluid Osmotic PressureForces into = Interstitial Hydrostatic Pressure + Blood Osmotic Pressure MAP at general Capillary – 30 - 35 mmHg but at glomerulus 55 mmHg - why? efferent arteriole narrower than afferent arteriole – won’t blow out capillary due to being wrapped by podocytesInterstitial Fluid Osmotic Pressure 1 mm Hg in most capillaries – 0 mmHg in kidney due to non-filtration of the plasma proteins

41. Blood osmotic pressure 26 mmHg in most capillaries but 30 mmHg in Glomerulus due to increased concentration of plasma proteins due to non-filtrationInterstitial fluid hydrostatic pressure 0 mmHg in most tissues but 15 mmHg in kidney due relative lack of lymphatics and the narrowness of the Proximal Convoluted Tubule compared to Bowman’s space.

42. Vascular Resistance in MicrocirculationAfferent and efferent arterioles offer high resistance to blood flowBlood pressure declines from 95mm Hg in renal arteries to 8 mm Hg in renal veins (in most other venules and veins it drops to 10 – 15 mm Hg)The reason is due to the two arteriole anatomy- one arteriole coming into the glomerulus (afferent arteriole) and one coming out (efferent arteriole) – the combination of these two resistors significantly drops the pressure

43. Vascular Resistance in MicrocirculationResistance in afferent arterioles:Protects glomeruli from fluctuations in systemic blood pressure – if blood pressure gets to high – vasoconstrict so as to not blowout the glomerular capillaries – if to low vasodilate to let more blood into glomerulus so Glomerular Filtration Rate does not drop.Resistance in efferent arterioles:Reinforces high glomerular pressure – vasoconstriction gives a better back pressureReduces hydrostatic pressure in peritubular capillaries – this provides a better suction pressure in the peritubular capillaries for reabsorption of water

44. Renal Blood Flow (RBF) – how much whole blood flows to both kidneys in a minute – generally about 25% of cardiac output – average 1250 ml per minuteRenal Plasma Flow (RPF)– since the glomerulus filters out the formed elements – then really what goes into Bowman’s capsule is filtered plasma RPF = RBF(1 − HCT) (Determined by Clearance of PAH)Glomerular Filtration Rate (GFR) – what is the amount of the plasma that is filtered in one minute – on average approximately 125 ml per minute (Determined by Clearance of Creatinine) Clearances to be Discussed LaterFiltration Fraction – what percentage of plasma is filtered in a minute FF = GFR / RPF x 100

45. Regulation of Glomerular FiltrationThree mechanisms control the GFR Renal autoregulation (intrinsic system) inside kidneyNeural controls (Extrinsic)Hormonal mechanism (the renin-angiotensin system)- ExtrinsicTHESE WILL BETTER BE DISCUSSED LATER

46. The start of Reabsorption in the Renal TubuleThe ultra-filtrate of the blood now enters the first tubule (small tube) which is the Proximal convoluted tubule (PCT) – its walls are lined with cuboidal epithelial cells with numerous microvilli (increase surface area for reabsorption) and mitochondria (lots of active transport – both primary and secondary) The speed at which the glomerulus filters blood is termed the Glomerular Filtration Rate which on average is 125 ml per minute so in a day you put on average over 200 + liters of filtrated blood into the kidneysYou only have 3 – 6 liters of blood so you can see that you must reabsorb most of your fluid back into the blood stream Thus the main job of the PCT is Reabsorption of much of your ultrafiltrate of the blood

47. Reabsorption in the PCTGenerally 100% of glucose, amino acids, lactate, vitamins, and other non-waste organic substances80% of filtered bicarbonate65% of sodium, water60% of chloride55% of potassiumAlmost all of the uric acid and 50% of the urea reabsorbed but later secreted

48. Tubular ReabsorptionTwo routes – transcellular or paracellularTranscellular – through the cellParacellular – between the cellsMost travel by transcellular - transported substances move through three membranes 1. Luminal and 2. basolateral membranes of tubule cells and 3. endothelium of peritubular capillariesCa2+, Mg2+, K+, and some Na+ are reabsorbed via paracellular pathways Chloride also is reabsorbed paracellular in the proximal part of PCT and transcellular in Distal partThe epithelial cells are linked by leaky tight junctions

49. Renal TubuleFigure 25.4b

50. Sodium Reabsorption: Primary Active TransportSodium reabsorption is almost always by active transportNa+ enters the tubule cells at the luminal membraneIs actively transported out of the tubules by a Na+-K+ ATPase pump

51. Figure 25.12

52. Sodium Reabsorption: Primary Active TransportFrom there it moves to peritubular capillaries due to:Low hydrostatic pressure (as a result of narrower efferent arteriole giving resistance)High osmotic pressure of the blood (as a result of increased concentration of plasma proteins – remember they were never filtered in glomerulus but water was taken out – thus increase in effective concentration of these proteinsNa+ reabsorption provides the energy and the means for reabsorbing most other solutes

53. Reabsorption by PCT CellsActive pumping of Na+ drives reabsorption of: Water by osmosis, aided by water-filled pores called aquaporins (obligatory water reabsorption)Aquaporins I are permanent residents of the PCT epithelial cells unlike in the DCT where they will be controlled by antidiuretic hormoneCations and fat-soluble substances by diffusion- as the water leaves the concentration of cations and fat soluble substances increase thus forcing diffusion of them – an example of solute following solventOrganic nutrients and selected cations by secondary active transport

54. Small proteins that mistakenly get filtered are removed by pinocytosis Secondary Transporters cause reabsorption of the most of the organic substances like glucose, amino acids, lactic acid, sulfate and phosphate The Secondary Transport substances are limited by a Transport Maximum (Tm) – the amount removed cannot exceed the amount of transport carriers – another term for this is to exceed renal thresholdH+ removal will be discussed later in my renal acid- base discussion

55. Figure 25.12

56. Non-reabsorbed SubstancesA transport maximum (Tm): Reflects the number of carriers in the renal tubules available Exists for nearly every substance that is actively reabsorbedWhen the carriers are saturated, excess of that substance is excreted – exceeds Tm or also termed exceeds renal threshold

57. Nonreabsorbed SubstancesSubstances are not reabsorbed if they: Lack carriers (secondary transport)Are not lipid solubleAre too large(and water soluble) to pass through membrane pores (thus electrolytes pass through membrane pores)Creatinine is an important non-reabsorbed substance (but its non- reabsorption is advantageous in medicine in that it can be used to determine the Glomerular Filtration RateGFR rate determination – discussed later

58. Figure 25.11

59. Figure 25.12

60. After the PCT comes the Loop of HenleLoop of Henle – a hairpin-shaped loop of the renal tubuleFunctions to further perform reabsorptionHelps with acid – base balance due to its Na+/H+ antiporters in the thick ascending limbA major function is the control of osmotic pressure as a result of its ability to concentrate the urineThe longer the loops (in juxtamedullary nephrons) the more the ability to concentrate the urine ( To be discussed later)

61. Parts of Loop of HenleProximal part is similar to the proximal convoluted tubule – and some refer to it as part of the PCT (pars recta of PCT) others refer to it as the descending thick limb of the Loop of HenleThen comes the descending thin limb which is lined by simple squamous cells. Its length varies depending on the location of nephrons in the cortex. Juxtamedullary nephrons have the longest thin limbs. Next is the bend (actual Loop) – then the ascending thin limbThen the ascending thick limb which is lined by short simple cuboidal cells – this area sometimes is termed the pars recta of the Distal Convoluted Tubule – in that it is similar in construct to the DCT

62. Renal TubuleFigure 25.4b

63. 63Reabsorption in the Loop of HenleThe loop of Henle sets the stage for independent regulation of both the volume and osmolarity of body fluids (reabsorption of substances can be selective in accordance with the body’s need for that substance and the body’s need to maintain the proper blood osmolarity (276 -300 mOsm).Na+-K+- 2Cl- symporters located in the ascending thick limb reclaim Na+, Cl-, and K+ ions from the tubular lumen fluid.Because K+ leakage channels return much of the K+ back into tubular fluid, the main effect of the Na+-K+-Cl- symporters is reabsorption of Na+ and Cl-.

64. Loop of HenleDescending thin limb of Loop of Henle totally permeable to water (aquaporins I) but mostly impermeable to solutes – thus water exits from tubule but few solutes – thus the intraluminal osmotic pressure gets highAscending limb – not at all permeable to water (no aquaporins) but very permeable to solutes (passive transport) additionally some active transport via–The 2 Cl-, Na+, K+ symporter

65. Ascending Limb of Loop of HenleOn basolateral side of the epithelial cells of the thick ascending limb has the sodium potassium pump creating a intracellular sodium concentration gradientOn the luminal side of the epithelial cells there is a symporter (secondary active transport) that uses sodium as the driver (energy provider) and carries 2 chlorides and one potassium in addition to the one sodiumAlso a Na+/H+ antiporter (This is used for acid/base balance discussed later)Some 50% of sodium exits via the paracellular route

66. 66Symporters in the Loop of HenleThick limb of loop of Henle has Na+ K- Cl- symporters that reabsorb these ionsK+ leaks through K+ channels back into the tubular fluid leaving the interstitial fluid and blood with a negative chargeCations passively move to the vasa recta

67. Loop of Henle Reabsorption35% of Chloride reabsorbed – leaving approximately 5% to be absorbed, if necessary, later (60% reabsorbed in the PCT) 20 – 30% of Na+ reabsorbed (leaving approximately 5 – 15% to be reabsorbed later- 65% in PCT) –depending on blood sodium levels and blood osmotic pressure- controlled by aldosterone 20 – 30% of K+ reabsorbed (leaving 15 – 25% to be absorbed later – 55% in PCT) depending on blood K+ levels in association with Na+ levels – again aldosterone

68. Loop of Henle Reabsorption Continued20 – 30% of Ca++ reabsorbed the amount left is reabsorbed later in the DCT in accordance with the blood calcium levels which are controlled by the hormones PTH & Calcitonin10 – 20% of HCO3- reabsorbed (leaving 0 – 10%) controlled by acid-base balance15% of H2O reabsorbed – leaving as much as 20% (65% removed in the PCT) – the amount left in tubules to be absorbed later as a result of the homeostatic control of Blood Osmotic Pressure. This is controlled by the hormones ADH and Aldosterone

69. Distal Convoluted Tubule (DCT)The DCT can be divided into a proximal portion and a very distal portion. The very distal portion leading into the Connecting Tubules has receptors for ADH and Aldosterone. The proximal portion does not. We will now examine the proximal portion

70. Renal TubuleFigure 25.4b

71. Proximal Portion of the DCTThe Proximal portion of the DCT has three regionsA) The Pars Recta which really is the continuation of the ascending thick limb of the Loop of HenleB) Pars Convoluta – which the official DCTC) Interposed at the junction between the Pars Recta and Pars Convoluta is a specialized region known as the Macula Densa (Dense spot of specialized cells)

72. DCTThe cells lining the DCT are short cuboidal cells with no microvilliThe DCT is not permeable to water or ureaThe DCT has Na+-Cl- symporters in the apical membrane – thus more Na+ and Cl- are reabsorbed from the filtrate in the tubuleIn the basolateral membranes Na+/K+ pumps acts as the driving force to operate the symportersAlso in basolateral surface are Cl- leak channels thus allowing Cl- to leak into the peritubular capillariesThe cells have Parathyroid Hormone receptors thus its stimulation causes passive reabsorption of Ca++

73. Reabsorption in the DCTAs fluid flows along the DCT, reabsorption of Na+ and Cl- continues due to Na+-Cl- symporters.Na+ and Cl- then reabsorbed into peritubular capillariesThe DCT serves as the major site where parathyroid hormone stimulates reabsorption of Ca+2.DCT is not very permeable to water so the solutes are reabsorbed with little accompanying water.

74. Filtrate Amounts Entering the DCT20% of the original filtrate of water enters the DCT15% - 25% of Potassium enters DCT5% - 15% of Sodium enters DCT5% of Chloride enters DCT 0 – 10% of Bicarbonate enters DCT10% - 20% of CalciumOverall the proximal part of the DCT automatically removes approximately 2% - 3% of the NaCl

75. Connecting TubulesThe distal convoluted tubules of several nephrons join to form a short connecting tubule that leads into the collecting duct (tubule)The distal portion of the distal convoluted tubule and the connecting tubules (as well as the collecting duct) have two types of specialized epithelial cells termed the Principal cells and the Intercalated cells.

76. Connecting TubulesTwo important cell types are found hereIntercalated cells (Type A & B)Cuboidal cells with microvilli Function in maintaining the acid-base balance of the bodyPrincipal cellsCuboidal cells without microvilliHelp maintain the body’s water and salt balance

77. Principal CellsThe Principal cells have receptors for ADH and AldosteroneThe DCT, Connecting Tubules and Collecting Duct are normally impermeable to water – they have no Aquaporins I. However, when stimulated by ADH they can carry in tiny membrane bound vesicles containing Aquaporins II. The vesicles fuse with the cell membrane inserting the Aquaporins II into the cell membrane of the Principal cells – thus opening channels to the reabsorption of water.

78. Principal CellsAldosterone stimulates the Principal Cells to insert more Na+/K+ exchangers in the cell’s apical surface and produce more Na+/K+ pumps on the basolateral surfaces – thus this causes the secretion into the luminal fluid of K+ and the reabsorption of Na+As a result of these actions - Aldosterone lowers blood potassium levels and raises blood sodium levels

79. Actions of the Principal CellsNa+ enters principal cellsthrough leakage channelsNa+ pumps keep theconcentration of Na+ inthe cytosol lowCells secrete variableamounts of K+, to adjustfor dietary changes in K+intakedown concentration gradient due to Na+/K+ pump Aldosterone increases Na+ and water reabsorption & K+ secretion by principal cells by stimulating the synthesis of new pumps and channels.

80. Collecting Duct (CD)The Collecting Duct is termed this because it collects modified filtrate from several nephronsIt has the same properties of the distal portion of the DCT and connecting tubules – principal cells and intercalated cellsIt is where true concentration of the urine can occur as a result of the counter-current multiplier system (to be discussed later) It is the last area in the kidney where the filtrate can be modified – thus once it leaves the CD it is officially urine

81. The Collecting Duct travels down through the cortex of the kidney then through the medullary portion of the kidney In the inner areas of the medullary portion of the kidneys – several collecting ducts come together to form Papillary Collecting Tubules (Ducts of Bellini). These Papillary Ducts open at the renal papillae – thus the urine then enters the minor calyx.

82. Nephron AnatomyFigure 25.5a

83. Summary of Absorptive Capabilities of Renal Tubules and Collecting DuctsSubstances reabsorbed in PCT include:Sodium, all nutrients, cations, anions, and waterUrea and lipid-soluble solutesSmall proteinsLoop of Henle reabsorbs:H2O, Na+, Cl, K+ in the descending limbCa2+, Mg2+, and Na+ in the ascending limb

84. Summary of Absorptive Capabilities of Renal Tubules and Collecting DuctsDCT absorbs:Ca2+, Na+, H+, K+, and waterHCO3 and ClCollecting duct absorbs:Water and urea

85. Juxtaglomerular Apparatus (JGA)The JGA is so named because it is piece of specialized renal anatomy juxta (next to) positioned to the glomerulusIt is composed of two structures the Juxtaglomerular cells of the afferent arteriole (sometimes efferent) in contact with the macula densa cells of the DCT

86. Juxtaglomerular CellsArteriole walls have juxtaglomerular (JG) cellsEnlarged, smooth muscle cells Have secretory granules containing reninAct as mechanoreceptors

87. Macula DensaMacula densaTall, closely packed distal tubule cells Lie adjacent to JG cells Function as chemoreceptors or osmoreceptorsMesangial cells: (previously mentioned but mentioned again on next slide) Have phagocytic and contractile propertiesInfluence capillary filtration

88. Mesangial CellsBetween the capillary loops of the glomerulus are Mesangial cells (intraglomerular) and some located at the vascular pole of the renal corpuscle (extraglomerular). The intraglomerular Mesangial cells are a) phagocytic thus cleaning the filter b) contractile in that they have receptors for vasoconstrictors like angiotensin II c) help support the capillaries in regions where the visceral layer of Bowman’s capsule does not come in contact with the capillaries.The extraglomerular mesangial cells are connected by gap junctions and may serve as a communication between macula densa and granular cells.

89. Juxtaglomerular Apparatus (JGA)Figure 25.6

90. Regulation of Glomerular FiltrationThe kidney attempts to maintain a normal GFR despite the body’s MAPIf the GFR is too high:Needed substances cannot be reabsorbed quickly enough and are lost in the urineIf the GFR is too low:Everything is reabsorbed, including wastes that are normally disposed of

91. Regulation of the Glomerular Filtration Rate (GFR)Three mechanisms control the GFR Renal autoregulation (intrinsic system)Neural controlsHormonal mechanism (the renin-angiotensin system)

92. Intrinsic ControlsUnder normal conditions, renal autoregulation maintains a nearly constant glomerular filtration rate – this system can work effectively as long as MAP is between 80 mmHg and 180 mmHg. During very low MAP like in hemorrhage it cannot work properly and must be overtaken by Extrinsic Controls. Autoregulation entails two types of controlMyogenic – responds to changes in pressure in the renal blood vessels – tonus of the smooth muscleFlow-dependent tubuloglomerular feedback – senses changes in the juxtaglomerular apparatus

93. Myogenic ToneIf too much pressure placed on the walls of the afferent arteriole (to fast of a blood flow) – vasoconstriction will occurIf too little pressure (too slow of a blood flow) – vasodilation will occur

94. Tubuloglomerular FeedbackThe Macula Densa in the wall of the DCT senses osmotic pressure and chemicalsIf the osmotic pressure is high and or the NaCl level is high – this suggests there is too fast of a flow into the tubules (it appears to the MD cells that there is not enough time for adequate reabsorption of solutes- thus too many solutes are still in modified filtrate) In this case the Macula Densa sends a vasoconstrictor substance (not sure what it is but think it is ATP) to the afferent arteriole to cause vasoconstriction of the AA – thus reducing blood flowIf too little osmotic pressure or NaCl then the opposite occurs

95. Autoregulatory mechanisms maintain a fairly constant GFR – if the MAP stays between 80 mm Hg and 180 mm Hg. When the MAP is too high or too low – must add in “Extrinsic Controls”

96. Extrinsic ControlsWhen the sympathetic nervous system is at rest:Renal blood vessels are maximally dilatedAutoregulation mechanisms prevail

97. Extrinsic ControlsUnder stress it is important to protect the MAP of the body, in particular the brain, this may be at the detriment of the kidneys:Norepinephrine is released by the sympathetic nervous systemEpinephrine is released by the adrenal medulla Both the afferent arterioles and efferent arterioles have Alpha1 receptors – the afferent arterioles have more Apha1 receptors than the efferent arterioles.

98. With little sympathetic stimulation such as at rest both the AA and EA are both maximally dilated. With moderate sympathetic stimulation the AA and EA are both marginally constricted to the same amount. With maximal sympathetic stimulation as during heavy exercise or hemorrhage, vasoconstriction of the Afferent arterioles predominates. This vasoconstriction causes a significant decrease in GFR – thus increasing the intravascular volume in the rest of the body. The sympathetic nervous system also stimulates the renin-angiotensin mechanism

99. Renin-Angiotensin MechanismIs triggered when the JG cells release reninRenin acts on angiotensinogen to release angiotensin I Angiotensin I is converted to angiotensin II Angiotensin II: Causes mean arterial pressure to rise Stimulates the adrenal cortex to release aldosterone As a result, both systemic and glomerular hydrostatic pressure rise

100. Actions of Angiotensin II (All cause an increase in MAP)1. Powerful vasoconstrictor2. Stimulates reabsorption of sodium both directly by acting on renal tubules and indirectly by stimulating the release of Aldosterone3. Stimulates release of ADH from posterior pituitary and stimulates thirst center4. Increases fluid reabsorption – thus increasing intravascular volume. AII decreases peritubular hydrostatic pressure because of vasoconstriction of efferent arterioles – thus more water goes into peritubular capillaries. Efferent arterioles have AII receptors.5. Works on mesangial cells causing them to contract – thus reducing cross sectional area of the glomerular capillaries. The decreases GFR.

101. Renin ReleaseRenin release is triggered by:Reduced stretch of the granular JG cellsStimulation of the JG cells by activated macula densa cells – possibly due to decreased ATP secretion and/or increased release of PGE2Direct stimulation by epinephrine and norepinephrine on the JG cells’ 1-adrenergic receptors (1 also on the heart)

102. Renin ReleaseFigure 25.10

103. Other Factors Affecting Glomerular FiltrationProstaglandins (PGE2 and PGI2)Vasodilators produced so as to counteract the actions of sympathetic stimulation and angiotensin II – the kidney needs to protect itself (keep some modicum of GFR even in the face of failing systemic BP.Are thought to prevent renal damage when peripheral resistance is increasedNitric oxide – vasodilator produced by the vascular endotheliumIntrarenal Angiotensin II – kidney produces some AII to oppose actions of PGE2Vasoconstrictors Adenosine – vasoconstrictor of renal vasculatureEndothelin – a powerful vasoconstrictor secreted by tubule cells

104. Atrial Natriuretic Peptide ActivityANP reduces blood Na+ which:Decreases blood volumeLowers blood pressureANP lowers blood Na+ by:Acting directly on medullary ducts to inhibit Na+ reabsorptionCounteracting the effects of angiotensin IIIndirectly stimulating an increase in GFR reducing water reabsorption

105. SecretionFiltration – was taking materials out of the blood and putting into the kidneys at Bowman’s capsuleReabsorption – was placing certain substances back into the blood – a recapturing processSecretion is removing certain unwanted substances from the blood that were not able to be filtered at the renal corpuscle (glomerulus & Bowman’s capsule)

106. Secretion Why? Not all the blood can be filtered into Bowman’s capsule on one pass through the kidneys (Filtration Fraction) – if it did we would lose all our blood volume temporarily into the kidneys. It would remain there until it could be reabsorbed back into the bloodstream in the proximal convoluted tubule – the efferent arteriole would have no blood and dry out. Thus blood borne waste and other substances desiring filtration must continue in the blood. These substances must travel throughout the entire circulation until they return to the kidneys for filtration on the second pass. The body does not want some of these substances to wait for a second pass – a role for secretion.

107. Tubular Secretion - Purposes1. Disposes of substances such as certain drugs and metabolites, that are tightly bound to plasma proteins. Because the plasma proteins are not generally filtered, these substances must be secreted.2. Elimination of undesirable substances or end products that have been reabsorbed by passive processes. Urea and uric acid are handled this way. Urea cycling will be discussed later. 3. Ridding the body of excess K+. Since most K+ is reabsorbed – it sometimes must be removed (prevent hyperkalemia) as a result of Aldosterone.4. Control of pH – secretion of H+ if needed

108. SecretionTubular secretion is the transfer of materials from peritubular capillaries to renal tubular lumen. Tubular secretion is caused mainly by active transport but sometimes facilitated diffusion as in urea recycling (to be discussed later).Usually only a few substances are secreted. These substances are present in great excess, or are natural poisons.Many drugs are eliminated by tubular secretion.

109. SecretionSubstances such as H+, K+, NH4+, creatinine, and certain organic acids either move into the filtrate from the peritubular capillaries or are synthesized in the tubule cells and secreted.Example of drugs secreted are penicillin, glucuronide, cimetidine.

110. GFR CalculationGFR is calculated using renal clearanceRC = UV/PRC = renal clearance rateU = concentration (mg/ml) of the substance in urineV = flow rate of urine formation (ml/min)P = concentration of the same substance in plasma

111. Renal Blood Flow (RBF) – how much whole blood flows to both kidneys in a minute – generally about 25% of cardiac output – average 1250 ml per minuteRenal Plasma Flow (RPF)– since the glomerulus filters out the formed elements – then really what goes into Bowman’s capsule is filtered plasma RPF = RBF(1 − HCT) Glomerular Filtration Rate (GFR) – what is the amount of the plasma that is filtered in one minute – on average approximately 125 ml per minute Filtration Fraction – what percentage of plasma is filtered in a minute FF = GFR / RPF x 100

112. Type of Substance Needed for GFR DeterminationOnly filtered not reabsorbed or secreted – thus only involves the filterFiltered in accordance with its concentration in the bloodClosest substance the body makes is CreatinineCreatinine is slightly secreted Inulin is the best substance – but the body does not make it

113. Creatine and CreatinineIn humans and animals, approximately half of stored creatine originates from food (mainly from fresh meat). Since vegetables do not contain creatine, vegetarians show lower levels of muscle creatine which, upon creatine supplementation, rise to a level higher than in meat-eaters.In humans, about half of the daily creatine is biosynthesized from three different amino acids - arginine, glycine, and methionine in the kidneys, pancreas and liver. The rest is taken in by alimentary sources. Ninety-five percent of creatine is later stored in the skeletal muscles (must be transported there).Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass).

114.

115. Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme expressed by various tissue types. It catalyses the conversion of creatine and consumes adenosine triphosphate (ATP) to create phosphocreatine and adenosine diphosphate (ADP).In tissues that consume ATP rapidly, especially skeletal muscle, but also brain and smooth muscle, phosphocreatine serves as an energy reservoir for the rapid regeneration of ATP. Thus creatine kinase is an important enzyme in such tissues.