Tubuloglomerular Feedback: Mechanism and Importance

Introduction:

The functional unit of the kidney is the nephron. The tubule returns to the parent glomerulus in each mammalian kidney nephron, producing the juxtaglomerular apparatus (JGA). The JGA has a different arrangement of glomerular afferent and efferent arterioles, extraglomerular mesangial cells, and specialized tubular epithelial cells known as the macula densa, the vascular smooth muscle cells, and the renin-secreting cells.

What Is the Significance of the Tubuloglomerular Contact Site?

• The high volume of fluid and electrolytes filtered from the glomeruli into the tubular system explains the functional significance of this tubuloglomerular contact point. This "glomerular leak" is a constant risk of excessive fluid and electrolyte loss.

• On a typical diet, only 0.5-one percent of the fluid or sodium is filtered in the glomeruli and expelled in the urine. The remaining 99-99.5 percent is reabsorbed along the tube and collecting the duct system.

• A five percent difference in glomerular filtration and consequent reabsorption would result in a net loss of nearly one-third of total extracellular fluid volume in one day, resulting in vascular collapse.

• On the other hand, renal salt retention exceeds the body's demands and plays a significant role in developing arterial hypertension.

• Apart from glomerulotubular balance, or the normal flow dependency of tubular reabsorption in each nephron segment, the juxtaglomerular apparatus contributes considerably to the fine coordination of glomerular filtration tubular reabsorption through the tubuloglomerular feedback mechanism (TGF).

What Is Tubuloglomerular Feedback Mechanism?

• The TGF mechanism is a series of processes in which alterations in the concentrations of Na+, Cl, and K+ in the tubular fluid are detected by the macula densa through the Na+-K+-2Cl cotransporter (NKCC2) in its luminal membrane.

• Increases or decreases in Na+, Cl, and K+ uptake induce variations inversely in glomerular filtration rate (GFR) through modifying vascular tone, particularly in the afferent arteriole.

• Because loop diuretics like furosemide block Na+-K+-2Cl cotransporter (NKCC2), they do not decrease GFR even if they raise the salt concentration at the macula densa, which adds to their powerful diuretic action.

• TGF keeps fluid and electrolyte transport to the distal nephron within specified limitations, allowing for subtle modifications in reabsorption or excretion in the distal nephron under the regulation of aldosterone and vasopressin. In this way, the TGF mechanism helps to maintain a proper balance between GFR and tubular reabsorption upstream of the macula densa.

• In the absence of primary alterations in reabsorption upstream from the macula densa, the TGF mechanism serves GFR autoregulation, a characteristic of kidney function, by altering GFR to maintain early distal tubular fluid and electrolyte supply.

What Are the Mediators of TGF in the Juxtaglomerular Apparatus?

• First, in a few seconds, the factor must produce vasoconstriction of the afferent arteriolar that continues in the presence of the mediator but quickly disappears when the mediators are removed.

• Secondly, the factor must be produced or discharged locally based on the luminal salt concentration at the macula densa. Because an increase in salt content at the macula densa is also linked with the inhibition of renin secretion, the factor should therefore have an inhibitory effect on renin release.

• Osswald and colleagues in 1980 postulated that adenosine may serve as a TGF mediator and that the idea of adenosine-mediated metabolic regulation of organ function could also relate to the kidney.

• Contrary to other organs, blood flow in the kidney cortex is predominantly responsible for glomerular filtration and, as a result, energy-utilizing transporting effort. In contrast to other organs, such as the heart or muscle, metabolic regulation of kidney function necessitates the presence of a renal cortical vasoconstrictor.

• Adenosine is an afferent arteriole vasoconstrictor, and persistent afferent arteriolar vasoconstriction after continuous adenosine administration into the renal artery causes a persistent drop in the total GFR of the total kidney and also superficial single nephrons susceptible to micro puncture.

• Furthermore, when adenosine is removed, vasoconstriction is immediate and transient.

What Is the Suggested Signal Transmission and TGF Mediation Mechanism?

• Cotransport-dependent ATP hydrolysis in macula densa cells (or tubular cells proximal to the juxtaglomerular apparatus) will increase AMP production. The formed AMP is dephosphorylated to adenosine in the cell through cytosolic 5′-nucleotidase or plasma membrane-bound endo-5′-nucleotidase.

• The formed adenosine is transported into the interstitium of the extraglomerular mesangium using a nucleoside transporter. Alternatively, AMP might escape the cell and be converted to adenosine in the interstitium by plasma membrane-bound ecto-5′-nucleotidase.

• α,β-methylene adenosine 5′-diphosphate (MADP), the 5′-nucleotidase inhibitor that suppressed TGF in the micropuncture tests, is thought to block plasma membrane-bound 5′-nucleotidase but not AMP-specific cytosolic 5′-nucleotidase.

• Thus, plasma membrane-bound ecto- or endo-5′-nucleotidase might produce the adenosine that mediates TGF. Extracellular adenosine then attaches to adenosine A1 receptors on the extraglomerular mesangial cell surface, increasing cytosolic Ca2+ concentrations.

• Gap junctions transport Ca2+ transients to target cells in the afferent arteriole, inhibiting the release of renin and vasoconstriction of the afferent arteriolar.

What Is the Relationship between TGF and the Salt Paradox of the Diabetic Kidney?

• Diabetes modifies the renal hemodynamic response to increased dietary NaCl consumption and generates baseline glomerular hyperfiltration. A modest NaCl consumption produces renal vasodilation and a rise in GFR, whereas an excessive NaCl intake generates the opposite effects.

• Miller validated the finding in 1997 in young type I diabetes patients who reacted to a low-salt diet with renal vasodilation and increased GFR.

• The kidney can adapt NaCl excretion to allow for various dietary NaCl consumption without alterations in renal blood flow and GFR, suggesting that the kidney primarily modifies NaCl excretion by adjusting tubular reabsorption.

• However, there are additional instances in which increased dietary NaCl intake raises GFR. If everything else is equal, increasing GFR will increase NaCl excretion; hence, increasing GFR can be part of the kidney's reaction to higher NaCl excretion.

• Yet, the deleterious effect of dietary NaCl on GFR in diabetes is paradoxical in terms of NaCl balance and hence referred to as the "salt paradox" of the diabetic kidney.

• Salt balance is preserved through aldosterone-controlled adaptation of NaCl reabsorption in the distal nephron downstream of the macula densa.

Conclusion:

Proper interaction between TGF and the renin-angiotensin system is critical for maintaining body fluid and electrolyte balance in the context of significant changes in daily salt consumption. Thus, changes in TGF may have a major role in the pathogenesis of various illnesses, including hypertension, diabetes, and congestive heart failure. The recent ideas might assist in finding novel targets for the avoidance of initial renal hemodynamic alterations in diabetes, which could avoid kidney damage further.