Targeted Delivery of Soluble Guanylate Cyclase (sGC) Activator Cinaciguat to Renal Mesangial Cells via Virus-Mimetic Nanoparticles Potentiates Anti-Fibrotic Effects by cGMP-Mediated Suppression of the TGF-β Pathway

URN to cite this document:

urn:nbn:de:bvb:355-epub-447477 Copy

DOI to cite this document:

10.5283/epub.44747 Copy

Göpferich, Achim ; Fleischmann, Daniel ; Harloff, Manuela ; Figueroa, Sara Maslanka ; Schlossmann, Jens

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Date of publication of this fulltext: 11 Mar 2021 08:37

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Details

Item type:	Article
Open Access Type:	Gold (with APC)
Höhe Gebühr (aus OpenAPC):	1974.01
Institution der Zahlung:	Regensburg U
Journal or Publication Title:	International Journal of Molecular Sciences
Publisher:	MDPI
Place of Publication:	BASEL
Volume:	22
Number of Issue or Book Chapter:	2557
Page Range:	pp. 1-18
Date:	4 March 2021
Institutions:	Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich)
Projects (Historical):	Open Access Publizieren (DFG), DFG GO 565/17-3
Identification Number:	Value Type 10.3390/ijms22052557 DOI
Keywords:	; sGC activators; cGMP; nanoparticle drug delivery; mesangial cells; diabetic nephropathy
Dewey Decimal Classification:	600 Technology > 615 Pharmacy
Status:	Submitted
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	44747

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Abstract

Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular hyperproliferation. These pathological effects are in part caused by an impaired ...

Abstract

Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular hyperproliferation. These pathological effects are in part caused by an impaired functionality of soluble guanylate cyclase (sGC) and a consequentially reduced synthesis of anti-fibrotic messenger 3 ',5 '-cyclic guanosine monophosphate (cGMP). Bay 58-2667 (cinaciguat) is able to re-activate defective sGC; however, the drug suffers from poor bioavailability and its systemic administration is linked to adverse events such as severe hypotension, which can hamper the therapeutic effect. In this study, cinaciguat was therefore efficiently encapsulated into virus-mimetic nanoparticles (NPs) that are able to specifically target renal mesangial cells and therefore increase the intracellular drug accumulation. NP-assisted drug delivery thereby increased in vitro potency of cinaciguat-induced sGC stabilization and activation, as well as the related downstream signaling 4- to 5-fold. Additionally, administration of drug-loaded NPs provided a considerable suppression of the non-canonical transforming growth factor beta (TGF-beta) signaling pathway and the resulting pro-fibrotic remodeling by 50-100%, making the system a promising tool for a more refined therapy of DN and other related kidney pathologies.

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Metadata last modified: 12 Jul 2022 05:55

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