NL
DE
Thiazolidinediones (TZDs) as agonists for the nuclear transcription factor, peroxisome proliferator-activated receptor ɣ (PPARɣ) ameliorate proteinuria in certain glomerular diseases, however, the underlying mechanisms remain elusive.
Baranca Buijsers, Tom Nijenhuis and Johan van der Vlag (Department of Nephrology), in collaboration with 3 other academic medical centers, UMCG, LUMC, and Amsterdam MC, published in April a paper in the open source Journal of Lancet, eBioMedicine, part of the Lancet Discovery Science section. The paper of Buijsers et al. further discloses the mechanisms underlying the protective effect of treatment with TZDs on kidneys in patients with kidney disease. The consortium showed that the expression of the glycocalyx-degrading enzyme heparanase is regulated by PPARy expression, which leads to proteinuria, and which is blunted by treatment with TZDs. Notably, the heparan sulfate-degrading enzyme, heparanase, is crucial for the degradation of glomerular endothelial glycocalyx and the development of proteinuria in most glomerular diseases.
The study revealed that heparanase is regulated by PPARy both in vitro, in cultured glomerular cells, and in vivo, in a rat model for glomerular disease. In humans treated with TZDs, plasma heparanase activity strongly tended to be decreased. The study showed that PPARɣ directly binds to specific sequences within the heparanase promotor region in both podocytes and glomerular endothelial cells. Notably, podocytes and glomerular endothelial cells are the main cellular parts of the glomerular filtration barrier.
Implications of the study are that PPARy-mediated regulation of heparanase expression adds a novel and crucial mechanism that explains the anti-proteinuric and kidney protective effects of TZDs in clinical practice.
Read the study here
Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria. Marjolein Garsen, Baranca Buijsers, Marloes Sol, Lena Gockeln, Ramon Sonneveld, Toin H. van Kuppevelt, Mark de Graaf, Jacob van den Born, Jan A.A.M. Kamps, Daniël H. van Raalte, Rutger W. van der Meer, Hildo J. Lamb, Jan-Luuk Hillebrands, Ton J. Rabelink, Marissa L. Maciej Hulme, Guido Krenning, Tom Nijenhuis, Johan van der Vlag.
