학술논문
Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria.
Document Type
Academic Journal
Author
Garsen M; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; Buijsers B; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; Sol M; Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.; Gockeln L; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; Sonneveld R; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; van Kuppevelt TH; Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; de Graaf M; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; van den Born J; Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, the Netherlands.; Kamps JAAM; Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.; van Raalte DH; Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.; van der Meer RW; Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.; Lamb HJ; Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.; Hillebrands JL; Division of Pathology, University Medical Center Groningen, Groningen, the Netherlands.; Rabelink TJ; Department of Nephrology and Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.; Maciej-Hulme ML; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; Krenning G; Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.; Nijenhuis T; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; van der Vlag J; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: Johan.vanderVlag@radboudumc.nl.
Source
Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE
Subject
Language
English
Abstract
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 development of proteinuria, whereas peroxisome proliferator-activated receptor ɣ (PPARɣ) agonists can ameliorate proteinuria. Since a recent study showed that PPARɣ regulates HPSE expression in liver cancer cells, we hypothesized that PPARɣ agonists exert their reno-protective effect by inhibiting glomerular HPSE expression.
Methods: Regulation of HPSE by PPARɣ 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 PPARɣ 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 PPARɣ 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 PPARɣ 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 transendothelial 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 PPARɣ 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: PPARɣ-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice.
Funding: This study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships).
Competing Interests: Declaration of interests The authors declare that there are no conflicts of interest.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Methods: Regulation of HPSE by PPARɣ 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 PPARɣ 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 PPARɣ 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 PPARɣ 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 transendothelial 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 PPARɣ 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: PPARɣ-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice.
Funding: This study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships).
Competing Interests: Declaration of interests The authors declare that there are no conflicts of interest.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)