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Tubuloglomerular feedback – Old and New

Tubuloglomerular feedback – Old and New. Dr. Overview. Introduction Tubuloglomerular feedback (TGF) Definition Past data Recent developments Information from genetically modified animals Conclusions. Introduction.

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Tubuloglomerular feedback – Old and New

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  1. Tubuloglomerular feedback – Old and New Dr.

  2. Overview • Introduction • Tubuloglomerular feedback (TGF) • Definition • Past data • Recent developments • Information from genetically modified animals • Conclusions

  3. Introduction • The juxtaglomerular apparatus (JGA) represents a functional and structural link between • 1) the macula densa (MD) cells, which represent specialized tubular cells at the end of the thick ascending limb of Henle’s loop, • 2) the cells of the extraglomerular mesangium, which fill the angle between the afferent and the efferent glomerular arteriole, and • 3) the vascular smooth muscle cells and renin-secreting cells in the media of the afferent glomerular arteriole News Physiol Sci 2003;18:169-174.

  4. Introduction (Contd) • In 1937, Goormaghtigh suggested that • The juxtaglomerular apparatus might participate in the maintenance of volume homeostasis by generating some sort of signal in response to changes in the composition of distal tubular fluid Kidney International 1990; 38:577—583.

  5. Introduction (Contd) • This hypothesis has been refined over the past four decades as • substantial experimental data have accrued to support the existence of an operational system of tubuloglomerular feedback (TGF)

  6. Introduction (Contd) • Juxtaglomerular apparatus • Significantly contributes to the fine coordination between glomerular filtration and tubular reabsorption through the mechanism of tubuloglomerular feedback (TGF) • Also maintains glomerulotubular balance, i.e., the normal flow dependence of tubular reabsorption in every nephron segment News Physiol Sci 2003;18:169-174.

  7. TGF • Changes in NaCl concentration in the tubular lumen near the tubulo-vascular contact point at the distal end of the ascending loop of Henle elicit adjustments in glomerular arteriolar resistance, • a phenomenon referred to as ‘tubuloglomerular feedback’ (TGF) News Physiol Sci 2003;18:169-174.

  8. TGF (Contd) • The TGF mechanism refers to • a series of events whereby changes in the Na+, Cl-, and K+ concentrations in the tubular fluid are sensed by the macula densa via the Na+-K+-2Cl cotransporter (NKCC2) in its luminal membrane News Physiol Sci 2003;18:169-174.

  9. TGF (Contd) • NKCC2 is inhibited by loop diuretics like furosemide, and therefore loop diuretics do not lower GFR even though they increase the salt concentration at the macula densa, which contributes to their potent diuretic effect News Physiol Sci 2003;18:169-174.

  10. TGF (Contd) • As a consequence of TGF, the fluid and electrolyte delivery to the distal nephron is kept within certain limits, which facilitates • the fine adjustments in reabsorption or excretion in the distal nephron under the control of aldosterone and vasopressin • In this regard, the TGF mechanism serves • To establish an appropriate balance between GFR and tubular reabsorption upstream from the macula densa

  11. TGF (Contd) • In the absence of primary changes in reabsorption upstream from the macula densa, by adjusting GFR to keep early distal tubular fluid and electrolyte delivery constant, the TGF mechanism also contributes to autoregulation of GFR, which is a hallmark of kidney function

  12. TGF (Contd) • An increase or decrease in Na+, Cl, and K+ uptake elicits inverse changes in glomerular filtration rate (GFR) by altering the vascular tone, predominantly of the afferent arteriole News Physiol Sci 2003;18:169-174.

  13. TGF (Contd) • Since increases in NaCl concentration cause increases of afferent arteriolar resistance and a fall in GFR, the system is constructed as a negative feedback loop that serves to keep NaCl delivery into the distal parts of the nephron within narrow boundaries

  14. Negative Feedback Control of GFR

  15. Renal Autoregulation of GFR •  BP  constrict afferent arteriole, dilate efferent •  BP  dilate afferent arteriole, constrict efferent • Stable for BP range of 80 to 170 mmHg (systolic) • Cannot compensate for extreme BP

  16. Renal Autoregulation of GFR (Contd) • Myogenic mechanism •  BP  stretches afferent arteriole  afferent arteriole constricts  restores GFR • Tubuloglomerular feedback • Macula densa on DCT monitors tubular fluid and signals juxtaglomerular cells (smooth muscle, surrounds afferent arteriole) to constrict afferent arteriole to  GFR

  17. GFR Regulation • Myogenic response • Similar to autoregulation in other systemic arterioles • Tubuloglomerular feedback • Hormones and autonomic neurons • By changing resistance in arterioles • By altering the filtration coefficient

  18. Juxtaglomerular Apparatus Figure 19-9

  19. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 4 1 5 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 4 Paracrine diffuses from macula densa to afferent arteriole. 5 Afferent arteriole constricts. Resistance in afferent arteriole increases. Collecting duct Hydrostatic pressure in glomerulus decreases. Loop of Henle GFR decreases. PLAY Animation: Urinary System: Glomerular Filtration Figure 19-10

  20. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 1 Afferent arteriole Granular cells Collecting duct Loop of Henle Figure 19-10, step 1

  21. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 1 Afferent arteriole Granular cells 2 2 Collecting duct Loop of Henle Figure 19-10, steps 1–2

  22. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 1 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 Collecting duct Loop of Henle Figure 19-10, steps 1–3

  23. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 4 1 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 4 Paracrine diffuses from macula densa to afferent arteriole. Collecting duct Loop of Henle Figure 19-10, steps 1–4

  24. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 4 1 5 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 4 Paracrine diffuses from macula densa to afferent arteriole. 5 Afferent arteriole constricts. Collecting duct Loop of Henle Figure 19-10, steps 1–5 (1 of 4)

  25. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 4 1 5 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 4 Paracrine diffuses from macula densa to afferent arteriole. 5 Afferent arteriole constricts. Resistance in afferent arteriole increases. Collecting duct Loop of Henle Figure 19-10, steps 1–5 (2 of 4)

  26. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 4 1 5 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 4 Paracrine diffuses from macula densa to afferent arteriole. 5 Afferent arteriole constricts. Resistance in afferent arteriole increases. Collecting duct Hydrostatic pressure in glomerulus decreases. Loop of Henle Figure 19-10, steps 1–5 (3 of 4)

  27. Tubuloglomerular Feedback Distal tubule Efferent arteriole Glomerulus Bowman’s capsule GFR increases. 1 Proximal tubule Macula densa 2 Flow through tubule increases. 4 1 5 3 Flow past macula densa increases. Afferent arteriole Granular cells 3 2 2 4 Paracrine diffuses from macula densa to afferent arteriole. 5 Afferent arteriole constricts. Resistance in afferent arteriole increases. Collecting duct Hydrostatic pressure in glomerulus decreases. Loop of Henle GFR decreases. Figure 19-10, steps 1–5 (4 of 4)

  28. TGF • TGF acts as a minute-to-minute stabilizer of distal salt delivery, thereby minimizing the impact of random perturbations in filtration and absorption forces on NaCl excretion

  29. Tubuloglomerular Feedback (Fig. 18-10, Silverthorn)

  30. TGF theory: beginning • Goormaghtigh, Harsing, and Thurau clearly recognized that the existence of a tubulovascular connection at the site of the macula densa (MD) provides an ideal pathway along which • Changes in the composition of the urine at that point can affect afferent arteriolar tone and thereby glomerular filtration rate (GFR) Kidney International 1998;54 (Suppl. 67):S40 –5

  31. TGF theory: beginning (Contd) • The site of the MD is particularly suited for the location of a chemoreceptor because [NaCl] at this site is hypotonic, variable, and determined almost exclusively by loop of Henle flow rate • Beginning with Thurau’s microinjection experiments, numerous investigators have now established firmly that GFR is in fact inversely related to [NaCl] at the MD Kidney International 1998;54 (Suppl. 67):S40 –5

  32. TGF theory: beginning (Contd) • Micropuncture has proven to be the most valuable tool in establishing the relationship between luminal NaCl concentration and glomerular filtration rate or glomerular capillary pressure, but this approach has major limitations in resolving the intermediate steps in the transmission pathway

  33. TGF adaptation • TGF helps to overcome inherent limitations of GTB (glomerulotubular balance) in stabilizing distal salt delivery • The added stability bestowed on nephron function by negative feedback from TGF inevitably incurs some cost in terms of less efficient salt homeostasis, • but this cost is tempered by TGF resetting Am Soc Nephrol 2008; 19: 2272–2275

  34. Function of the juxtaglomerular apparatus (JGA). (A) Short-term function. With random high-frequency perturbations, macula densa (MD) [NaCl] and glomerular filtration rate (GFR) oscillate around a set point, whereas plasma renin does not change. (B) Long-term function of the JGA. With prolonged perturbations exceeding the operating range of the tubuloglomerular feedback (TGF) mechanism, plasma renin changes concomitantly with resetting of the TGF function curve. Resetting permits stabilization of MD [NaCl] and GFR at a new operating point. Kidney International 1998;54, Suppl. 67: S40 –S45.

  35. TGF profiles vary according tophysiological circumstance Kidney International 1990; 38:577—583.

  36. What is the mediator of TGF in the JGA? • The mechanism(s) by which the macula densa cells transform the luminal signal, i.e., the luminal Na+, Cl-, and K+ concentrations at the macula densa, into one or more mediators that alter afferent arteriolar tone is still incompletely understood News Physiol Sci 2003;18:169-174.

  37. What are the requirements for a mediator of the TGF response? • First • Within seconds the factor must induce an afferent arteriolar vasoconstriction that persists in the presence of the mediator but rapidly vanishes when the mediator is withdrawn • Second • The factor must be generated or released locally, depending on the luminal salt concentration at the macula densa • Because a rise in the salt concentration at the macula densa is in addition associated with an inhibition of renin secretion, the factor should also have an inhibitory action on renin release if the factor mediates both responses News Physiol Sci 2003;18:169-174.

  38. TGF • The TGF response is complex • Requiring coordinated functional changes in epithelial, mesangial, and smooth muscle cells, and delineation of the cellular mechanisms responsible for linking the NaCl input with the vascular endpoints has been relatively slow News Physiol Sci 2003;18:169-174.

  39. TGF: Recent advances • The use of gene-manipulated mice has generated a new venue to further explore the mechanisms responsible for TGF Kidney Int. 2008 August ; 74(4): 418–426.

  40. TGF: Recent advances (Contd) • Substantial experimental evidence supports the notions that • luminal NaCl concentration initiates TGF responses by changes in tubular NaCl transport, and that the • signal arising from changes in NaCl transport is transmitted across the juxtaglomerular interstitium by the generation of paracrine messengers Kidney Int. 2008 August ; 74(4): 418–426.

  41. TGF: Recent advances (Contd) • The availability of animals with defined transport deficits and with targeted deficiencies in the generation or action of potential mediators has permitted new insights in both of these areas of TGF function Kidney Int. 2008 August ; 74(4): 418–426.

  42. NaCl transport • Apical NaCl uptake - NKCC2 • There is general agreement that the primary mechanism mediating the transduction of luminal NaCl concentration into a propagated signal across the juxtaglomerular interstitium is activation of the Na,K,2Cl-cotransporter, NKCC2, in the apical membrane of MD cells • This basic tenet rests on the observation that a number of loop diuretics including furosemide, bumetanide, piretanide, ethacrynic acid, triflocin, or l-ozolinone produce complete TGF inhibition, and on the good quantitative agreement between the inhibitor concentrations causing half-maximal inhibition of transport and TGF Kidney Int. 2008 August ; 74(4): 418–426.

  43. NaCl transport (Contd) • Apical NaCl uptake - NKCC2 • TGF-mediated reductions of GFR and filtered NaCl have been observed in both NHE3-/- and AQP1-/- mice, and it has been surmised that reductions in filtered NaCl load by TGF are a major reason for the ability of mice with proximal transport defects to achieve Na balance Kidney Int. 2008 August ; 74(4): 418–426.

  44. NaCl transport (Contd) • Apical NaCl uptake - NKCC2 • In contrast, mice with complete inactivation of the NKCC2 gene display the severe salt-losing phenotype of antenatal Bartter syndrome Kidney Int. 2008 August ; 74(4): 418–426.

  45. NaCl transport (Contd) • Apical NaCl uptake - NKCC2 • In vivo microperfusion of loops of Henle showed that in NKCC2B-deficient mice Cl reabsorption was significantly reduced at low flow rates, while the lack of NKCC2A resulted in reduced Cl- absorption at high perfusion rates • These in vivo data are in line with the notion that TAL reabsorption at low NaCl concentrations relies on the activity of the highCl--affinity NKCC2B isoform while NKCC2A comes into play under when higher salt concentrations are achieved by high loop perfusion flow Kidney Int. 2008 August ; 74(4): 418–426.

  46. Relationship between loop of Henle perfusion rate and the percentage reduction of stop flow pressure (± SEM), an expression of TGF responsiveness, in mice lacking NKCC2B (circles) or NKCC2A (dots). Dashed lines indicate position of V1/2, the flow rates causing half maximum reduction of PSF

  47. NaCl transport (Contd) • Apical NaCl uptake - NKCC2 • Assessment of TGF responses has confirmed that macula densa signaling function depends on the successive engagement of NKCC2B and NKCC2A Kidney Int. 2008 August ; 74(4): 418–426.

  48. NaCl transport (Contd) • Apical NaCl uptake – ROMK • Whereas the inhibitory effect of luminal barium on TGF responses was diminished by a pronounced direct vascular constrictor action, retrograde application of the K+ channel blocker U37883A caused an almost complete inhibition of TGF responsiveness Kidney Int. 2008 August ; 74(4): 418–426.

  49. NaCl transport (Contd) • This effect is mediated by ROMK type K+ channels since TGF responses were largely absent in mice with targeted ROMK deletion Kidney Int. 2008 August ; 74(4): 418–426.

  50. NaCl transport (Contd) • The observation that inhibition of NKCC2 and ROMK has similar effects on TGF responses argues against a specific “sensor” function of the actual transport proteins suggesting instead a critical role of some consequence of MD NaCl transport • Since ambient distal K+ concentrations near the MD are close to the K+ affinity of the cotransporter variations in luminal K+ may regulate TGF response magnitude Kidney Int. 2008 August ; 74(4): 418–426.

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