Background Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential for the... Show moreBackground Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential for the development of proteinuria, whereas peroxisome proliferator-activated receptor y (PPARy) agonists can ameliorate proteinuria. Since a recent study showed that PPARy regulates HPSE expression in liver cancer cells, we hypothesized that PPARy agonists exert their reno-protective effect by inhibiting glomerular HPSE expression.Methods Regulation of HPSE by PPARy was assessed in the adriamycin nephropathy rat model, and cultured glomerular endothelial cells and podocytes. Analyses included immunofluorescence staining, real-time PCR, heparanase activity assay and transendothelial albumin passage assay. Direct binding of PPARy to the HPSE promoter was evaluated by the luciferase reporter assay and chromatin immunoprecipitation assay. Furthermore, HPSE activity was assessed in 38 type 2 diabetes mellitus (T2DM) patients before and after 16/24 weeks treatment with the PPARy agonist pioglitazone.Findings Adriamycin-exposed rats developed proteinuria, an increased cortical HPSE and decreased heparan sulfate (HS) expression, which was ameliorated by treatment with pioglitazone. In line, the PPARy antagonist GW9662 increased cortical HPSE and decreased HS expression, accompanied with proteinuria in healthy rats, as previously shown. In vitro, GW9662 induced HPSE expression in both endothelial cells and podocytes, and increased trans -endothelial albumin passage in a HPSE-dependent manner. Pioglitazone normalized HPSE expression in adriamycin-injured human endothelial cells and mouse podocytes, and adriamycin-induced transendothelial albumin passage was reduced as well. Importantly, we demonstrated a regulatory effect of PPARy on HPSE promoter activity and direct PPARy binding to the HPSE promoter region. Plasma HPSE activity of T2DM patients treated with pioglitazone for 16/24 weeks was related to their hemoglobin A1c and showed a moderate, near significant correlation with plasma creatinine levels.Interpretation PPARy-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice.Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Preeclampsia is a syndrome of pregnancy characterised by hypertension and proteinuria and occurs in up to 5 percent of pregnant women. The pathophysiology of preeclampsia has not been fully... Show morePreeclampsia is a syndrome of pregnancy characterised by hypertension and proteinuria and occurs in up to 5 percent of pregnant women. The pathophysiology of preeclampsia has not been fully elucidated yet. The endothelium is known to play a key role in the pathogenesis and levels of vascular endothelial growth factor are decreased due to an angiogenic imbalance. In the first part of this thesis, genes associated with preeclampsia were investigated through meta-analysis; genes within the coagulation and immunology domains remained significantly associated with preeclampsia after meta-analysis. In the second and third part of this thesis, the possible role of a key regulator of coagulation and immunology on the endothelium, thrombomodulin, in preeclampsia was investigated in the placenta and the kidney. Diminished placental thrombomodulin expression was associated with the angiogenic imbalance of preeclampsia. Next, in the fourth part of this thesis the interplay between podocytes and endothelial cells in the glomerulus during the anti-angiogenic conditions in preeclampsia was reviewed. In the final part of this thesis the splicing pattern of vascular endothelial growth factor was investigated throughout different examples of glomerular disease. Show less