Does evidence suggest that urinary angiotensinogen originates from proximal tubular cells in the kidney?

Origin of Urinary Angiotensinogen from Proximal Tubular Cells

Yes, evidence strongly suggests that urinary angiotensinogen primarily originates from proximal tubular cells in the kidney, with some contribution from filtered plasma angiotensinogen. 1, 2

Evidence for Proximal Tubular Origin

Cellular Markers and Production

• Proximal tubular cells express specific marker proteins including megalin, cubilin, aminopeptidase, and aquaporin-1 (AQP1), which help identify their contribution to urinary components 1
• These cells actively synthesize angiotensinogen, as demonstrated by both in vitro studies and in vivo models 2, 3
• Direct evidence shows that proximal convoluted tubule (PCT) cells in culture produce both angiotensinogen and renin-like activity, while proximal straight tubule (PST) cells produce angiotensinogen 3

Urinary Extracellular Vesicles (uEVs) Analysis

• Proteomic analysis of urinary extracellular vesicles confirms that uEVs originate from kidney epithelial cells of the nephron, including proximal tubular cells 1
• The presence of proximal tubular cell-specific markers in these vesicles provides evidence that components like angiotensinogen from these cells reach the urine 1

Dual Source Mechanism

While proximal tubular cells are the primary source, there is a dual mechanism for urinary angiotensinogen:

1. Direct synthesis by proximal tubular cells:

   • The S3 segment of proximal tubules actively synthesizes angiotensinogen 4
   • This production is regulated by sodium intake, angiotensin-II levels, and inflammatory cytokines 4

2. Reabsorption of filtered angiotensinogen:

   • Liver-derived angiotensinogen from plasma can be filtered at the glomerulus 5
   • Filtered angiotensinogen is reabsorbed by proximal tubular cells through megalin-mediated endocytosis 5
   • In the S1 and S2 segments, angiotensinogen may primarily derive from the systemic circulation 4

Clinical Significance

• Urinary angiotensinogen levels correlate with intrarenal renin-angiotensin system activity 6

• Elevated urinary angiotensinogen is associated with:

  • Hypertension and proteinuria 6
  • Chronic kidney disease progression 6
  • Early diabetic nephropathy (even in the premicroalbuminuric phase) 7

• Overexpression of angiotensinogen in proximal tubules can lead to:

  • Hypertension
  • Enhanced reactive oxygen species generation
  • Tubular apoptosis
  • Tubulointerstitial fibrosis 2, 4

Important Considerations

• Disruption of the glomerular filtration barrier in kidney diseases increases filtration of plasma angiotensinogen, contributing to elevated urinary levels 5
• RAS blockers significantly attenuate urinary angiotensinogen levels, suggesting therapeutic implications 7
• Urinary angiotensinogen may serve as a potential biomarker for intrarenal RAS activity and early detection of kidney disease 6, 7

The evidence clearly demonstrates that proximal tubular cells play a central role in urinary angiotensinogen production, though with some contribution from filtered plasma angiotensinogen, particularly in disease states with increased glomerular permeability.