Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease

Abstract

Current drugs used to treat proteinuric disorders of the kidney have been borrowed from other branches of medicine, and are only partially effective. The discovery of a central, mechanistic role played by two different forms of the secreted glycoprotein angiopoietin-like 4 (Angptl4) in human and experimental glomerular disease has opened new treatment avenues. Localized upregulation of a hyposialylated form (lacks sialic acid residues) of Angptl4 secreted by podocytes induces the cardinal morphological and clinical manifestations of human minimal change disease, and is also being increasingly recognized as a significant contributor toward proteinuria in experimental diabetic nephropathy. Oral treatment with low doses of N-acetyl-D-mannosamine, a naturally occurring precursor of sialic acid, improves sialylation of Angptl4 in vivo, and reduces proteinuria by over 40%. By contrast, a sialylated circulating form of Angptl4, mostly secreted from skeletal muscle, heart and adipose tissue in all major primary glomerular diseases, reduces proteinuria while also causing hypertriglyceridemia. Intravenous administration of recombinant human Angptl4 mutated to avoid hypertriglyceridemia and cleavage has remarkable efficacy in reducing proteinuria by as much as 65% for 2 weeks after a single low dose. Both interventions are mechanistically relevant, utilize naturally occurring pathways, and represent new generation therapeutic agents for chronic kidney disease related to glomerular disorders.

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…The sialylation form of ANGPTL4 produced in podocytes interacts with αvβ5 intergrin in glomerular endothelial cells to govern glomerulus structure and stability 41. Blockade of this interaction could postpone the recovery from peak proteinuria in mice models of kidney diseases 41, 42. Furthermore, on the one hand, ANGPTL4 promotes endothelial cell integrity and improves angiogenesis for cerebral protection in ischemic stroke; on the other hand, upregulation of ANGPTL4 in hypoxic Müller cells accelerates abnormal angiogenesis and retinopathy 43.…”

Nephrotic Syndrome

“…13 The added dimension of podocyte-secreted proteins is their ability to reach out to binding partners on the surface of glomerular endothelial cells and potentially participate in feedback loops within the glomerulus. 14 In addition to podocyte-secreted proteins, high plasma levels of the soluble urokinase receptor are being investigated for their role in the pathogenesis of FSGS. 15 A new dimension recently added to this field is the systemic response to proteinuria when it reaches nephrotic range.…”

“…Only the link between proteinuria and hypertriglyceridemia has been clearly elucidated. 12,14 This relationship is strongly influenced by the link between FFA and albumin. FFAs are a major fuel source for skeletal muscle and heart, and they are stored in adipose tissue as triglycerides.…”

“…14,25 An important lesson learned from Angptl4 is its "Jekyll and Hyde" effect, because the same protein can have very different biologic effects on the basis of the presence or absence of sialic acid residues and the compartment in which it is secreted. Because circulating sialylated Angptl4 has an antiproteinuric effect, it is conceivable that injecting recombinant human Angptl4 or increasing the secretion of native Angptl4 from heart, skeletal muscle, and adipose tissue using PPAR agonists, glucocorticoids, FFA supplements, or b-adrenergic agonists could be of potential benefit in reducing proteinuria through the systemic feedback loop.…”

“…14 The effects of hyposialylated Angptl4 are most likely related to its binding to the GBM, 11 but adverse consequences of glomerular endothelial binding are also possible. 12 Converting hyposialylated Angptl4 to sialylated protein using N-acetyl-D-manosamine, a precursor of sialic acid that can be taken up and stored in podocytes, very significantly reduces proteinuria and has the potential for use in small maintenance doses to prevent relapse in MCD and as maintenance therapy for diabetic nephropathy.…”