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Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome


The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4–β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.

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Figure 1: Elevated circulating Angptl4 levels are required for the development of hypertriglyceridemia in nephrotic syndrome.
Figure 2: The source of circulating Angptl4 in nephrotic syndrome.
Figure 3: Mechanisms of Angptl4 upregulation in peripheral organs in nephrotic syndrome.
Figure 4: Effect of circulating Angptl4 on proteinuria.
Figure 5: Circulating Angptl4 reduces proteinuria through its interaction with glomerular endothelial αvβ5 integrin.
Figure 6: Pathobiology of circulating Angptl4 in nephrotic syndrome.


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We thank investigators of the FSGS clinical trial for providing baseline plasma and urine samples from patients with FSGS; M. del Nogal-Avila (University of Alabama at Birmingham (UAB)) for selected real-time PCR studies; H. Donoro (UAB) for assistance with animal colony management; E. Soria (Instituto Nacional de Cardiologia) for immunogold electron microscopy studies; H. Chung (UAB) for advice on LPL assays; V. Kumar (UAB) for help in collecting Institutional Review Board–approved patient sera from transplant patients; D. Salant (Boston University) for γ2-NTS; A. Köster (Eli Lilly) for Angptl4−/− mice; M. Mitsuyama (Kyoto University) for Buffalo Mna rats; J. Brunzell (University of Washington) for 5D2 monoclonal antibody; F. Danesh (MD Anderson Cancer Center) for cultured rat glomerular endothelial cells; UAB–University of California-San Diego George O'Brien Center Core C for measuring urine and serum creatinine by mass spectrometry; UAB Nephrology Research and Training Center for equipment use; and UAB Research Foundation for filing patent PCT/US2011/039255 for the use of ANGPTL4 mutants as therapeutic agents for nephrotic syndrome. This work is supported by the US National Institutes of Health (R01DK077073 and R01DK090035 to S.S.C., K01DK096127 to L.C.C. and T32DK007545 to C.M.).

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L.C.C. maintained transgenic rat colonies and conducted rat experiments, developed stable cell lines and conducted imaging studies and selected gene expression studies. C.M. maintained the Itgb5−/− mouse colony and conducted mouse studies, did assays for Angptl4, V5-tagged proteins, triglycerides and free fatty acids and performed two-dimensional gel studies, western blotting, selected gene expression studies, protein interaction studies and albumin depletion studies. C.A.-C. interpreted and analyzed light microscopy, electron microscopy and immunogold electron microscopy studies. J.A.J. obtained blood and tissue from Nagase rats and provided useful advice on Nagase rat biology. S.K. conducted experiments with Angptl4−/− mice and made substantial contributions to the preparation and revision of the manuscript. S.S.C. acted as senior investigator, planned and supervised the study, generated mutant ANGPTL4 constructs to develop stable cell lines, conducted selected gene expression and animal studies and wrote and revised the manuscript with input from other authors.

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Correspondence to Sumant S Chugh.

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Competing interests

S.S.C. is founder, president and chief executive officer of GDTHERAPY LLC and has filed patents related to the use of ANGPTL4 mutants (PCT/US2011/039255) and precursors of sialic acid, including ManNAc (PCT/US2011/039058), for the treatment of nephrotic syndrome. S.S.C. may benefit financially from these patents in the future.

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Clement, L., Macé, C., Avila-Casado, C. et al. Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med 20, 37–46 (2014).

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