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

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 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.

Soluble guanylate cyclase stimulator reduced the gastrointestinal fibrosis in bleomycin-induced mouse model of systemic sclerosis

“…The authors showed that overexpression of sGCα1 and sGCα1 in MDA-MB-231 cells suppressed cell proliferation, induced apoptosis, and disturbed cell cycle progression and that sGC induced G1 and G2 cell cycle arrest in the cells. In another report on renal fibrosis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MMT) assay revealed that sGC activator significantly suppressed cell proliferation of mesangial cells [29]. It was also revealed that activation of the sGC-sGMP cascade resulted in suppression of hyperproliferation of mesangial cells and decreased the levels of pro-fibrotic markers [29].…”

“…In another report on renal fibrosis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MMT) assay revealed that sGC activator significantly suppressed cell proliferation of mesangial cells [29]. It was also revealed that activation of the sGC-sGMP cascade resulted in suppression of hyperproliferation of mesangial cells and decreased the levels of pro-fibrotic markers [29]. Therefore, cell growth inhibitory effects of sGC might be involved in the suppression of BLM-induced gastrointestinal hyperproliferative and prefibrotic response in this study.…”

Nutraceutical Prevention of Diabetic Complications—Focus on Dicarbonyl and Oxidative Stress

“…The bioactivity of eNOS-generated NO is impaired not only by eNOS uncoupling, but also by a direct quenching of NO by superoxide, yielding the unstable oxidant peroxynitrite. NO-mediated stimulation of soluble guanylate cyclase (sGC) and consequent production of cyclic GMP (cGMP) plays an important role in the prevention of diabetic nephropathy, neuropathy, cardiomyopathy and the endothelial dysfunction promoting atherosclerosis, as can be judged by the fact that treatment with drugs that directly stimulate sGC or that inhibit phosphodiesterase-5 (PDE-5, which selectively degrades cGMP) is protective with respect to these complications in rodent diabetes models [ 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 ]. High doses of the B vitamin biotin likewise have potential in this regard, as, in pharmaceutically feasible concentrations about a hundred-fold higher than the physiological plasma level, biotin can serve as an agonist for sGC [ 227 , 228 , 229 , 230 , 231 , 232 ].…”

Editorial of the Special Issue: cGMP-Signaling in Cells and Tissues: Molecular, Functional and Pharmacological Aspects

“…A novel aspect of pharmacological treatment would be the selective targeted delivery of the drug into specific cells. This principle was used by Fleischmann et al The sGC activator cinaciguat was selectively targeted to renal mesangial cells by designed viral mimetic nanoparticles, which could offer novel possible treatment options for chronic kidney diseases and renal fibrosis [ 5 ].…”