Targeted delivery of celastrol to glomerular endothelium and podocytes for chronic kidney disease treatment

Abstract

The etiology of chronic kidney disease (CKD) is complex and diverse, which could be briefly categorized to glomerular- or tubular-originated. However, the final outcomes of CKD are mainly glomerular sclerosis, endothelial dysfunction and injury, and chronic inflammation. Thus, targeted delivery of drugs to the glomeruli in order to ameliorate glomerular endothelial damage may help alleviate CKD and help enrich our knowledge. The herb tripterygium wilfordii shows therapeutic effect on kidney disease, and celastrol (CLT) is one of its active ingredients but with strong toxicity. Therefore, based on the unique structure and pathological characteristics of the glomerulus, we designed a targeted delivery system named peptides coupled CLT-phospholipid lipid nanoparticles (PC-PLNs) to efficiently deliver CLT to damaged endothelial cells and podocytes in the glomerulus for CKD treatment and research. PC-PLNs could effectively inhibit inflammation, reduce endothelial damage, alleviate CKD severity, and reduce the toxicity of CLT. We also studied the mechanism of CLT in the treatment of nephropathy and found that CLT can increase the level of NO by increasing eNOS while inhibiting the expression of VCAM-1, thus provides an anti-inflammatory effect. Therefore, our study not only offered an efficient CKD drug formulation for further development, but also provided new medical knowledge about CKD. Electronic Supplementary Material Supplementary material (attached with all the supporting tables and figures mentioned in this work) is available in the online version of this article at 10.1007/s12274-021-3894-x.

β-Cyclodextrin-based supramolecular nanoparticles: pH-sensitive nanocarriers for the sustained release of anti-tumor drugs

“…The hemolysis ratio of CSL/SBE 7 -b-CD/HDBAC was calculated to be B0.5%, which was lower than the safety level of biomaterials (5%). 49 The above results confirmed that CSL/SBE 7 -b-CD/HDBAC possesses favorable blood compatibility which ensures its safety in blood.…”

Network Pharmacology and Experimental Validation to Explore That Celastrol Targeting PTEN is the Potential Mechanism of Tripterygium wilfordii (Lév.) Hutch Against IgA Nephropathy

“… 41 Celastrol has recently been proven to restrain cancers, obesity, and inflammation. 22 , 42 , 43 Recent research has demonstrated that celastrol can treat CKD, 44 obesity-associated nephropathy 45 and mesangioproliferative glomerulonephritis 46 by acting as an anti-inflammatory agent and inhibiting the production of cytokines. Celastrol has also been shown to be effective in regulating insulin resistance and autophagy in diabetic nephropathy.…”

Nanomedicine in kidney disease

“…To address this issue, nanoparticles targeted to inflamed glomerular endothelium were loaded with a traditional Chinese root extract possessing anti-inflammatory effects, which reduced kidney disfunction and proteinuria in advanced IgA nephropathy. The anti-inflammatory properties were shown to be driven by increased eNOS expression and reduced VCAM-1 expression [14 ▪ ].…”