Megalin: A bridge connecting kidney, the renin-angiotensin system, and atherosclerosis

Abstract

Megalin is a member of the low-density lipoprotein receptor superfamily. It has been recognized as an endocytic receptor for a large spectrum of ligands. As a consequence, megalin regulates homeostasis of many molecules and affects multiple physiological and pathophysiological functions. The renin-angiotensin system is a hormonal system. A number of studies have reported contributions of the renin-angiotensin system to atherosclerosis. There is evolving evidence that megalin is a regulator of the renin-angiotensin system, and contributes to atherosclerosis. This brief review provides contemporary insights into effects of megalin on renal functions, the renin-angiotensin system, and atherosclerosis.

Keywords: Atherosclerosis; Kidney; Megalin; Renin angiotensin system.

Figure 1.. Roles of megalin during embryonic development.

Whole body deletion of megalin leads to lung insufficiency, neurological complications, and cardiovascular abnormalities during embryonic development, but has no apparent effects on renal development [14-16, 19, 21].

Figure 2.. Distribution pattern of megalin in proximal tubules.

Representative images of immunohistochemistry for megalin in a mouse kidney section. Red color represents positive immunostaining of megalin. Negative control was applied with an isotype matched non-immune IgG replacing megalin antibody. Scale bar = 50 μm.

Figure 3.. Inhibition of megalin ablates Western diet-induced proximal tubule pathology.

Hematoxylin-eosin staining was performed in kidney sections from LDL receptor deficient mice fed a Western diet (TD.88137, Envigo) for 12 weeks and administered either vehicle or megalin ASO. Cytosolic vacuolar formation in proximal tubules is abundant in mice injected with vehicle, but is not evident in mice injected with megalin ASO. Small boxes show higher magnification images. Scale bar = 50 μm.

Figure 4.. Presence of megalin, angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) in renal proximal tubules.

Immunofluorescent staining shows the location of megalin, AGT, renin, and ACE in proximal tubules of a mouse kidney section. In a mouse administered vehicle, megalin lies on the apical surface of proximal tubule cells, while AGT and renin are present intracellularly, and ACE is on the brush border membrane. Negative control (lack of megalin) is provided in a kidney section from a mouse administered megalin ASO. Megalin = green, AGT/ACE = red, renin = white, DAPI (nucleus) = blue. Scale bar = 10 μm. Images were adopted and modified from the authors’ publication [5].

Figure 5.. Proposed effects of megalin on the renal renin-angiotensin system and atherosclerosis.

Megalin is present on the apical surface of proximal tubule cells (PTCs) that regulates the homeostasis of AGT, renin, and AngII in PTCs. The process of these renin-angiotensin components in PTCs is proposed to contribute to the cross-talk between megalin and the renal RAS to promote atherosclerosis.