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

• Published in: International journal of molecular sciences Vol. 22; no. 5; p. 2557
• Main Authors: Fleischmann, Daniel, Harloff, Manuela, Maslanka Figueroa, Sara, Schlossmann, Jens, Goepferich, Achim
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.03.2021; MDPI
• Subjects: Animals; Benzoates - administration & dosage; Benzoates - pharmacokinetics; Bioavailability; Biomimetic Materials; Cells, Cultured; cGMP; Cyclic GMP; Cyclic GMP - metabolism; Diabetes; Diabetes mellitus; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Drug delivery; Drug Delivery Systems; Endothelium; Enzyme Activation - drug effects; Enzyme Stability - drug effects; Extracellular matrix; Fibrosis; Growth factors; Guanylate cyclase; Humans; Hyperglycemia; Hypotension; Kidneys; Kinases; Long-term effects; Mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; Mesangial Cells - pathology; Models, Biological; nanoparticle drug delivery; Nanoparticles; Nanoparticles - administration & dosage; Nephropathy; Nitric oxide; Oxidative stress; Pathological effects; Rats; sGC activators; Signal transduction; Signal Transduction - drug effects; Soluble Guanylyl Cyclase - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; sGC activators; cGMP; mesangial cells; diabetic nephropathy; nanoparticle drug delivery
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22052557

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 β (TGF-β) 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.