Tubuloglomerular feedback

Explain how the myogenic mechanism and tubuloglomerular feedback are responsible for autoregulation of renal blood flow... 

Tubuloglomerular feedback. Tubuloglomerular feedback involves the activity of the juxtaglomerular apparatus (see Figure 19.1). This structure is located where the distal tubule comes into contact with the afferent and efferent arterioles adjacent to the glomerulus. The juxtaglomerular apparatus is composed of the following ... 

The macula densa, which is involved in tubuloglomerular feedback, is also a factor in the regulation of renin secretion. In fact, this mechanism involving the macula densa is thought to be important in the maintenance of arterial blood pressure under conditions of decreased blood volume. For example, a decrease in blood volume leads to a decrease in RBF, GFR, and filtrate flow through the distal tubule. The resulting decrease in the delivery of NaCl to the macula densa stimulates the secretion of renin. Increased formation of angiotensin II serves to increase MAP and maintain blood flow to the tissues. 

Increased delivery of salt to the TAL leads to activation of the macula densa and a reduction in glomerular filtration rate (GFR) by tubuloglomerular (TG) feedback. The mechanism of this feedback is secretion of adenosine by macula densa cells, which locally causes afferent arteriolar vasoconstriction. This vasoconstriction reduces GFR. Tubuloglomerular feedback-mediated reduction in GFR exacerbates the reduction that was initially caused by decreased cardiac output. Recent work with adenosine receptor antagonists (eg, rolofylline) has shown that it will soon be possible to circumvent this complication of diuretic therapy in heart failure patients. Using rolofylline with a diuretic will make it possible to produce an effective diuresis in patients with heart failure without causing renal decompensation. 

Fig. 12.1 Main structural components of the nephron. Note particularly how the terminal part of the loop of Henle passes within cellular distances of the afferent arteriole. This forms the anatomical basis for the tubuloglomerular feedback mechanism by which the nephron regulates the incoming blood flow in response to variations in the ionic composition of the fluid that leaves the loop of Henle.

The delay in the tubuloglomerular feedback is represented by means of three first-order coupled differential equations ... 

Our next problem concerns the dynamic response of the arteriolar system to the signal from the mascula densa cells. This response is restricted to that part of the afferent arteriole that is closest to the glomerulus. Hence, the afferent arteriole is divided into two serially coupled sections of which the first (representing a fraction (3 of the total length) is assumed to have a constant flow (or hemodynamic) resistance, while the second (closer to the glomerulus) is capable of varying its diameter and hence the flow resistance in dependence of the tubuloglomerular feedback activation ... 

Fig. 12.5 One-dimensional bifurcation diagram for the single-nephron model obtained by varying the slope a of the open-loop response characteristics, r is the normalized arteriolar radius. The delay in the tubuloglomerular feedback is T = 16 s.

A Dynamic Model of the Tubuloglomerular Feedback Mechanism, Am. J. Physiol. 258, F1448-F1459 (1990). 

Complex factors maintain constancy of renal blood flow and glomerular filtration despite widely varying arterial pressures. Such factors such as the renal nervous system, prostaglandins, angiotensin 11, adenosine, tubuloglomerular feedback as well as other factors... 

ATP depletion, cation shifts and oxygen-derived free radical injury Site of renal ischemia-reperfusion injury A link between proximal and distal tubular injury and recovery Tubuloglomerular feedback and autoregulation Endothelin in ischemia-reperfusion injury Treatment of ischemic acute kidney injury Nephrotoxic injury Cyclosporine... 

To date, the in vitro perfused juxtamedullary nephron preparation has not been used to examine the effects of nephrotoxic agents. However the preparation has been used to examine the pathophysiology of tubuloglomerular feedback. It has also been used to study the effect of mediators like adenosine, oxygen radicals and nitric oxide. Some recent studies are discussed below. 

Angiotensin type 1A receptor knockout mice AT(1 A) receptors enhance tubuloglomerular feedback-mediated afferent arteriola constriction, in part by reducing the counteracting effect of nNOS [229]... 

Na-i-K-i-2CI- (NKCC) cotransporter inhibitors, furosemideand bumetanide. NKCC modulation alters vasoconstrictorby a mechanism that does not involve tubuloglomerular feedback responses [259]... 

Ichihara A, Flayashi M,KouraY,TadaY, SugayaT, Flirota N, SarutaT Blunted tubuloglomerular feedback by absence of angiotensin type 1A receptor involves neuronal NOS. Flypertension 40 934-939, 2002... 

Abbreviations renal blood flow (RBE), renal plasma flow (RPE), glomerular filtration rate (GFR), single nephron glomerular filtration rate (SNGFR), tubuloglomerular feedback (TGF). 

Thomson SC, Blantz RC. Homeostatic efficiency of tubuloglomerular feedback in hydropenia, euvolemia, and acute volume expansion. Am J Physiol 1993 264(6 Pt 2) F930-6. 

Schnermann J, Wright FS, Davis JM, Stackerberg WV, Grill G. Regulation of superficial nephron filtration rate by tubuloglomerular feedback. Pfiugers Arch 1970 318 147-75. 

Better OS, Rubinstein i, Winaver JM, Knochel JP. Mannitol therapy revisited (1940-1997). Kidney int 1997 51 886-894. Goldwasser P, Fotino S. Acute renal failure following massive mannitol infusion Appropriate response of tubuloglomerular feedback Arch intern Med 1984 144 2214-2216. 

Acetazolamide, and probably other diuretics which inhibit carbonic anhydrase, cause a strong inhibition of proximal NaHCOg reabsorption and lithium reabsorption. However, unlike loop diuretics, acetazolamide does not interfere with tubuloglomerular feedback and causes a 20% decrease in glomerular filtration rate. The increase in absolute lithium excretion is somewhat lower than that caused by loop diuretics [22]. Colussi et al. [25] reported the effect of furosemide and acefazola-mide to be additive, indicating a dual site of action (i.e., inhibition of lithium reabsorption in both the proximal tubule and the loop of Henle). 

Toward the end of the first week of continuous thmjr with a CA inhibitor, resistance develops to its diuretic ti feci. This is primarily due lo two factors. First, there s. marked reduction in the filtered load of HCOr because ib CA inhibitors produce both a 2O0f reduction in the Gfl via the tubuloglomerular feedback mechanism, and a Rste-tion in the plasma concentration of HCO3. When Iheit less HC0.3 present in the luminal fluid, there is less HCO reabsorption to inhibit. Second, the metabolic acklixsiscn ated by these diuretics provides a sufficient amouni it... 

The result of the combination of myogenic mechanisms and tubuloglomerular feedback is that the net filtration pressure or Pccap is kept reasonably constant over a very wide range of systemic arterial pressures. It should be noted that renal blood flow and GFR change across this range of systemic pressures but to a significantly smaller extent than would be predicted if these autoregulatory mechanisms were not in place. 

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