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.
Daniel FleischmannManuela HarloffSara Maslanka FigueroaJens SchlossmannAchim GoepferichPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- diabetic nephropathy
- transforming growth factor
- induced apoptosis
- high glucose
- drug delivery
- signaling pathway
- cell cycle arrest
- extracellular matrix
- epithelial mesenchymal transition
- drug induced
- systemic sclerosis
- idiopathic pulmonary fibrosis
- endoplasmic reticulum stress
- nitric oxide
- type diabetes
- end stage renal disease
- endothelial cells
- cardiovascular disease
- pi k akt
- cell death
- ejection fraction
- immune response
- newly diagnosed
- cell proliferation
- adipose tissue
- peritoneal dialysis
- protein kinase
- skeletal muscle
- bone marrow
- toll like receptor