Tubuloglomerular feedback – Old and New

Tubuloglomerular feedback – Old and New
Dr.

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

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:

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.

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)

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:

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:

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:

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:

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

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

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:

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

Negative Feedback Control of GFR

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

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

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

Juxtaglomerular Apparatus
Figure 19-9

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

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

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

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

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

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

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

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

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

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

(Fig , Silverthorn)

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

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

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

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

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.

TGF profiles vary according to physiological circumstance
Kidney International 1990; 38:577—583.

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:

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:

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:

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

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 August ; 74(4): 418–426.

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 August ; 74(4): 418–426.

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 August ; 74(4): 418–426.

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 August ; 74(4): 418–426.

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 August ; 74(4): 418–426.

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 August ; 74(4): 418–426.

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

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 August ; 74(4): 418–426.

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 August ; 74(4): 418–426.

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

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 August ; 74(4): 418–426.

Other theories Apical NaCl uptake - Na/H exchanger Basolateral NaCl extrusion - Na,K-ATPase Na extrusion - H(Na)/K-ATPase Kidney Int August ; 74(4): 418–426.

Scheme of TGF operation as supported by evidence mostly derived from studies in gene manipulated mice. Solid arrows indicate positive/stimulatory, and broken arrows negative/ inhibitory relationships. The depiction of cellular components is not meant to be complete, but to indicate those proteins for which a role in TGF is suggested by experimental evidence from gene-manipulated mice.

Signal Mediation Adenosine
In experimental series TGF responses were completely abolished in the A1AR-deficient mice, indicating that Adenosine, as the endogenous agonist of A1AR, is required for TGF responses to occur A1AR: A1 adenosine receptors Kidney Int August ; 74(4): 418–426.

Signal Mediation (Contd)
Adenosine It has been proposed that adenosine is produced and released by macula densa cells as a byproduct of increased NaCl transport and ATP utilization the available experimental evidence suggests that a major part of the adenosine required for local A1AR activation is derived from the dephosphorylation of released ATP Kidney Int August ; 74(4): 418–426.

Adenosine A direct role of ATP as a vasoconstrictor in the TGF signaling pathway may be possible, but the evidence for this is currently not compelling Kidney Int August ; 74(4): 418–426.

Adenosine Successive dephosphorylation of ATP or ADP to AMP by NTPDase 1 and from AMP to adenosine by ecto-5′-nucleotidase appears to provide most of the adenosine required for TGF responsiveness Kidney Int August ; 74(4): 418–426.

Nitric oxide The high levels of expression of neuronal NOS in macula densa cells has stimulated extensive investigations of the role of nitric oxide in juxtaglomerular signaling Kidney Int August ; 74(4): 418–426.

Nitric oxide Data suggest that the chronic absence of a functional nNOS in macula densa cells is associated with an enhanced vasoconstrictor tone in the subnormal flow range, presumably a consequence of a proportional enhancement of pre and postglomerular resistances Kidney Int August ; 74(4): 418–426.

Nitric oxide TGF responses have been found to be absent in mice with concurrent deficiencies in nNOS and A1AR indicating that nNOS deficiency does not overcome the lack of A1AR signaling This observation reaffirms the primacy of A1AR signaling and a modulating role of nitric oxide in the TGF pathway Kidney Int August ; 74(4): 418–426.

Proposed scheme for signal transmission and mediation of TGF
Numbers in circles refer to the following sequence of events. 1: concentration-dependent uptake of Na+,K+, and Cl by Na+-K+-2Cl cotransporter in maculadensa cells; 2: intra- or extracellular generation ofadenosine (ADO) involving 5’-nucleotidase; 3: ADO activates adenosine A1 receptors, triggering an increase in cytosolic Ca2+ in extraglomerular mesangial cells (MC); 4: the intensive coupling between extraglomerular MC, granular cells containing renin, and smooth muscle cells of the afferent arteriole (VSMC) by gap junctions allows propagation of the increased Ca2+ signal, resulting in afferent arteriolar vasoconstriction and inhibition of renin secretion. Local angiotensin II (ANG II) and neuronal nitric oxide synthase (NOS I) activity modulate this response. News Physiol Sci 2003;18:

TGF: More recent findings..
Vasodilatory adenosine A2b receptors in the 'efferent' TGF response Role of proximal tubular microvilli as mechanosensors in the flow-dependent tubular reabsorption as a mechanism to explain glomerulotubular balance Current Opinion in Nephrology & Hypertension 2010; 19(1):59-64

TGF: Diabetes mellitus
TGF-mediated dynamic and steady-state control of nephron filtration rate in diabetes mellitus The physiological role and the pathophysiological importance of TGF can be illustrated in diabetes mellitus, which today is a leading cause of end-stage renal disease News Physiol Sci 2003;18:

TGF: Diabetes mellitus (Contd)
The pathogenesis of diabetic nephropathy is poorly understood, but an important role can be ascribed to glomerular hyperfiltration, which is associated with reduced afferent arteriolar resistance and which occurs early in the course of diabetes News Physiol Sci 2003;18:

The following outlines the dual effect of diabetes on TGF, namely 1) impaired TGF-mediated dynamic autoregulation and 2) TGF-mediated steady-state glomerular hyperfiltration News Physiol Sci 2003;18:

TGF and the salt paradox of the diabetic kidney salt paradox may result from an enhanced NaCl sensitivity of transport upstream from the macula densa through the normal action of TGF News Physiol Sci 2003;18:

A: role of TGF in glomerular hyperfiltration in early diabetes mellitus.
Hyperglycemia causes a primary increase in proximal tubular NaCl reabsorption through enhanced Na+-glucose cotransport and tubular growth (1). The enhanced reabsorption rates reduce the TGF signal at the macula densa ([Na,Cl,K]MD) (2) and, via TGF, increase the single-nephron glomerular filtration rate (SNGFR) (3). The resulting glomerular hyperfiltration serves to partly restore the fluid and electrolyte load to the distal nephron, but at the same time it initiates and/or maintains development of diabetic nephropathy. B: the normal kidney adjusts NaCl transport to dietary NaCl intake primarily downstream of the macula densa, and thus [Na,Cl,K]MD or SNGFR are not altered. C: In contrast, diabetes renders reabsorption in the proximal tubule sensitive to dietary NaCl (1) with subsequent effects on the luminal TGF signal (2) and SNGFR (3). This explains the paradoxical effect of dietary NaCl on glomerular filtration rate in early diabetes News Physiol Sci 2003;18:

Conclusions Notwithstanding the complexity of salt balance at a molecular level, the overall salt homeostasis is simple Various natritropic nerves and hormones stabilize any disturbance in salt balance

Conclusions (Contd) A change in glomerular filtration rate (GFR) brought about by these natritropes will be partially counteracted by the impact of TGF on nephron function Thus, by stabilizing GFR, TGF reduces the usefulness of GFR as an instrument of salt balance, and lessens the efficiency of salt homeostasis

Conclusions (Contd) Taken together, evidence from studies in genetically modified mice has resulted in a fairly robust mechanistic framework of TGF operation Metabolic activation of epithelial cells resulting from increased transcellular NaCl transport mediated by NKCC2, ROMK and Na,KATPase is coupled to ATP release and extracellular adenosine formation; this in turn leads to activation of A1AR and vasoconstriction

Conclusions (Contd) Several other paracrine factors interact with this pathway to set vascular sensitivity Since this scheme identifies a considerable number of testable (and still untested) hypotheses, further utilization of gene manipulated mice will remain a useful strategy to enhance the understanding of juxtaglomerular signaling mechanisms

Conclusions (Contd) The presented concepts of glomerular hyperfiltration and of the salt paradox in early diabetes mellitus illustrate the principle role of TGF in stabilizing the fluid and electrolyte delivery to the distal nephron as well as its potential impact on the control of renal hemodynamics, making nephron filtration rate a “slave” to tubular function when the latter exhibits primary changes

Conclusions (Contd) These concepts may help to identify new targets for the prevention of early renal hemodynamic changes in diabetes that might avert later damage to the kidney

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