Nephrotic syndrome: components, connections, and angiopoietin-like 4-related therapeutics

Abstract

Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), and lipiduria. Each component has been investigated individually over the past four decades with some success. Studies published recently have started unraveling the molecular basis of proteinuria and its relationship with other components. We now have improved understanding of the threshold for nephrotic-range proteinuria and the pathogenesis of hypertriglyceridemia. These studies reveal that modifying sialylation of the soluble glycoprotein angiopoietin-like 4 or changing key amino acids in its sequence can be used successfully to treat proteinuria. Treatment strategies on the basis of fundamental relationships among different components of nephrotic syndrome use naturally occurring pathways and have great potential for future development into clinically relevant therapeutic agents.

Keywords: FSGS; diabetic nephropathy; lipids; nephrotic syndrome; podocyte; proteinuria.

Figure 1.

The nephrotic syndrome tree is shown. The trunk depicts increasing proteinuria, and the branches represent other components that appear when proteinuria crosses the nephrotic-range threshold.

Figure 2.

Schematic illustration of the two sources of FFA available for uptake by skeletal muscle, heart, and adipose tissue in the normal and nephrotic state. Green shows normal conditions, and red illustrates changes in nephrotic syndrome. The balance shifts significantly to albumin-bound FFA because of retention of albumin with high FFA content in nephrotic syndrome. Angptl4 secreted from these organs reduces the conversion of triglycerides to FFA by inactivating LPL, thereby reducing use of triglycerides and resulting in hypertriglyceridemia.

Figure 3.

Schematic illustration of negative feedback loops in the link between proteinuria, hypoalbuminemia, and hypertriglyceridemia mediated by Angptl4 and FFA. Plasma FFAs are noncovalently bound to albumin. Because of the preferential loss of albumin with low FFA content in nephrotic syndrome, there is a relative increase in circulating albumin with higher FFA content. Because glomerular disease progresses to severe proteinuria, hypoalbuminemia develops, and the combination of high albumin FFA content and lower plasma albumin levels increases the FFA-to-albumin ratio. It promotes entry of FFA into skeletal muscle, heart, and adipose tissue, which causes upregulation of Angptl4 at least partially mediated by PPARs. Angptl4 secreted from these organs participates in two feedback loops. In the systemic loop, it binds to glomerular endothelial α_vβ₅ integrin and reduces proteinuria. In a local loop, it inactivates LPL in the same organs from which it is secreted to reduce the uptake of FFA, thereby curtailing a stimulus for its own upregulation. Reproduced from reference , with permission.