Albumin overload activates intrarenal renin-angiotensin system through protein kinase C and NADPH oxidase-dependent pathway

J Hypertens. 2011 Jul;29(7):1411-21. doi: 10.1097/HJH.0b013e32834786f0.


Objective: Inappropriate activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the pathogenesis of hypertension and renal injury. However, the underlying mechanisms remain elusive. Proteinuria has been shown to elicit the renal activation of RAS. The present study was performed to test the intracellular signal pathway involved in albumin-triggered activation of RAS.

Design and methods: NRK52E cells, a rat renal proximal tubular cell line, were incubated with increased levels of albumin. The rat model of protein overload was established in female Wistar-Kyoto rats that were subjected to unilateral nephrectomy followed by daily intraperitoneal injection of BSA at various doses (0.5, 1.0, and 5.0 g/kg) or combination with intragastric administration of apocynin (100 mg/kg per day), an inhibitor of NADPH oxidase.

Results: Exposure of the cells to high levels of albumin activated the RAS through the endocytic receptors megalin and cubilin. High levels of albumin triggered the production of intracellular reactive oxygen species by a protein kinase C (PKC)-NADPH oxidase-dependent pathway and this, in turn, led to activation of nuclear factor-κB (NF-κB) and activation protein-1 (AP-1). Inhibition of PKC or NADPH oxidase abolished albumin-induced activation of RAS. In a protein overload rat model, activation of RAS in renal proximal tubular cells was significantly increased, coincident with activation of PKC, NADPH oxidase, NF-κB, and AP-1. Chronic inhibition of NADPH oxidase by apocynin largely ameliorated intrarenal activation of RAS.

Conclusion: Exposure of renal tubular epithelial cells with high levels of albumin triggers activation of RAS via a PKC-NADPH oxidase-dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / administration & dosage*
  • Animals
  • Cell Line
  • Female
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / metabolism*
  • NADPH Oxidases / metabolism*
  • Protein Kinase C / metabolism*
  • Rats
  • Rats, Inbred WKY
  • Renin-Angiotensin System*


  • Albumins
  • NADPH Oxidases
  • Protein Kinase C