What is the effect of angiotensin II (Angiotensin 2) levels on tubuloglomerular feedback (TGF)?

From the Guidelines

Angiotensin II plays a crucial role in enhancing tubuloglomerular feedback sensitivity, which is essential for maintaining glomerular filtration rate and regulating blood pressure. The pathophysiology of renal blood flow impairment, as described in the study by 1, highlights the importance of angiotensin II in mediating the degree of renal blood flow impairment. Key points to consider include:

• Angiotensin II-induced efferent arteriolar vasoconstriction helps maintain glomerular filtration rate
• The use of ACE inhibitors or angiotensin II receptor blockers can cause acute renal failure in patients with bilateral renal artery stenoses or stenosis to a solitary kidney
• The glomerular filtration rate falls, but renal blood flow changes very little, resulting in a decreased filtration fraction The study by 1 provides valuable insights into the pathophysiology of renal blood flow impairment, but it does not directly address the effect of angiotensin II on tubuloglomerular feedback. However, based on the available evidence, it can be inferred that angiotensin II enhances tubuloglomerular feedback sensitivity, making this renal autoregulatory mechanism more responsive to changes in distal tubular sodium chloride delivery. This is crucial for maintaining glomerular filtration rate within a narrow range and preventing excessive sodium and water loss during states of volume depletion. Mechanistically, angiotensin II achieves this effect by enhancing the signaling between the macula densa cells and the afferent arteriole, primarily through increased production of adenosine and other vasoactive mediators. Additionally, angiotensin II directly constricts the efferent arteriole more than the afferent arteriole, which helps maintain glomerular filtration pressure even during states of decreased renal perfusion. This dual action on tubuloglomerular feedback and arteriolar tone is crucial for the kidney's ability to regulate blood pressure and fluid balance during various physiological challenges.

From the Research

Effect of Angiotensin 2 on Tubular Glomerular Feedback

• Angiotensin II (Ang II) has been shown to enhance connecting tubule glomerular feedback (CTGF) by activating Ang II type 1 receptors, protein kinase C, and epithelial Na channels (ENaC) in the connecting tubule 2.
• The study found that adding Ang II to the connecting tubule lumen increased the maximal response of the afferent arteriole and decreased the concentration of NaCl needed to achieve half maximal response.
• The effect of Ang II on CTGF was blocked by losartan, an Ang II type 1 antagonist, and by the protein kinase C inhibitor staurosporine, but not by PD123319, an Ang II type 2 antagonist 2.
• Another study found that Ang II levels are regulated by angiotensin-converting enzyme 2 (ACE2), which degrades Ang II and forms angiotensin 1-7 (Ang 1-7), a peptide that opposes the actions of Ang II 3.
• Increased Ang II levels can upregulate ACE2 activity, and ACE2 deficiency can lead to increased Ang II levels and decreased Ang 1-7 levels 3.

Regulation of Angiotensin 2 Levels

• Angiotensin II levels are also regulated by the renin-angiotensin-aldosterone system (RAAS), which can be inhibited by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) 4.
• ACE inhibitors and ARBs have been shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria 4.
• However, dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes and has predisposed patients to serious adverse events 4.

Intrarenal Angiotensin II Levels

• Intrarenal angiotensin II levels are much higher than circulating angiotensin II levels, and are responsible for regulating renal hemodynamics and tubular transport 5.
• The high intrarenal angiotensin II levels are caused by the presence of angiotensinogen messenger RNA and protein in the proximal tubule cells, and by positive amplification of angiotensin II production and secretion 5.
• The ability of the kidney to generate high intratubular and interstitial concentrations of angiotensin II allows the kidney to regulate intrarenal levels in accord with the homeostatic needs for the regulation of renal hemodynamics and tubular reabsorption 5.