Objective- AGT (
Angiotensinogen) is the unique precursor of the renin-angiotensin system that is sequentially cleaved by
renin and ACE (
angiotensin-converting enzyme) to produce Ang II (
angiotensin II). In this study, we determined how these
renin-
angiotensin components interact with
megalin in kidney to promote
atherosclerosis. Approach and Results- AGT,
renin, ACE, and
megalin were present in the renal proximal convoluted tubules of wild-type mice. Hepatocyte-specific AGT deficiency abolished AGT
protein accumulation in proximal tubules and diminished Ang II concentrations in kidney, while
renin was increased.
Megalin was most abundant in kidney and exclusively present on the apical side of proximal tubules. Inhibition of
megalin by
antisense oligonucleotides (ASOs) led to ablation of AGT and
renin proteins in proximal tubules, while leading to striking increases of urine AGT and
renin concentrations, and 70% reduction of renal Ang II concentrations. However, plasma Ang II concentrations were unaffected. To determine whether AGT and
megalin interaction contributes to
atherosclerosis, we used both male and female
low-density lipoprotein receptor-/- mice fed a saturated fat-enriched diet and administered vehicles (PBS or control ASO) or
megalin ASO. Inhibition of
megalin did not affect plasma
cholesterol concentrations, but profoundly reduced atherosclerotic lesion size in both male and female mice. Conclusions- These results reveal a regulatory role of
megalin in the intrarenal
renin-
angiotensin homeostasis and
atherogenesis, positing renal Ang II to be an important contributor to
atherosclerosis that is mediated through AGT and
megalin interactions.