Fluorescent Angiotensin II uptake by proximal tubular cells in culture.
Because the angiotensin-converting enzyme (ACE) is responsible for most Ang II synthesis in vivo, we have used pharmacological and genetic approaches to determine the specific contributions of kidney ACE-derived Ang II to hypertension. We reported that mice expressing ACE only in the kidneys, and no other tissues, become hypertensive after chronic Ang I (One) infusion. These findings were paired with significant increases in intrarenal Ang II content and significantly correlated with urinary Ang II excretion.
In our current project, we use two genetic models of kidney-specific ACE inhibition. In these experiments we show that the absence of kidney ACE confers substantial protection against experimental hypertension. We are also expanding our observations to the more clinical question of whether increased intrarenal ACE-derived Ang II synthesis induces salt-sensitivity. Salt sensitivity affects 50% of all patients with essential hypertension, and virtually all cases in which the hypertension is caused by renal parenchymal disease, yet the underlying mechanisms are unknown.
Surface plasmon resonance (SPR) analysis of angiotensin II-megalin interaction. Top: Shown in the figure are the results of 2 superimposed experiments performed in separate times. Bottom: SPR analysis of ANG II-megalin and ANG II-cubilin interactions. Am J Physiol Renal Physiol 2005;288:F420-F427.