Nano-Sustained CO-Releasing Molecules Alleviates Cyclosporin-A-Induced Nephrotoxicity and Renal Fibrosis by Inhibiting NLRP3 Inflammasome-Mediated TGF-β/Smad Signaling Pathway
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Renal fibrosis



Submitted : 2023-05-01
Accepted : 2023-05-16
Published : 2023-05-31


Objective: To investigate the effect nano-sustained CO-releasing molecules on cyclosporin-A (CsA)-induced nephrotoxicity by inhibiting the NLRP3 inflammasome-mediated TGF-β/Smad signaling pathway. Methods: 3×105 cell/mL human renal tubular epithelial cells (HK-2) and mouse primary cultured renal tubular epithelial cells (RTECs) were cultured under an inverted microscope and incubated with 10% DMEM and 0.25% β2M in NaCl solution for 3 h. HK-2 and RTECs were divided into 5 complex numbers. MTT assay was used to detect the relative proliferation level of one of the HK-2 cells and calculate the multiplication ratio. Results: The nano-sustained CO-releasing molecules CS-CO had a strong protective effect on the kidney. HK-2 and RTECs cells were treated with siRNA, inhibitors, and NLRP3 knockout mice, and the changes in cell activity and expression of intracellular inflammatory factors were studied. The expression of TGF-β1/Smad signaling pathway related proteins in HK-2 and RTECs was detected by ELISA, western blot, immunofluorescence, and other techniques. Conclusion: SMA/CORM2 alleviates CsA-induced renal fibrosis by inhibiting NLRP3 inflammasome-mediated TGF-β/Smad signaling pathway.


Tian RF, Li PS, 2022, IFN-? Combined with TNF-? Stimulates Mesenchymal Stem Cells to Relieve Cisplatin- Induced Renal Fibrosis. China Science and Technology Papers Online Quality Papers, 15(03): 318–327.

Jiang Y, 2022, Coenzyme Q10 Inhibits Rip1-RIP3-MLK l- Mediated Necrotic Apoptosis Through Wnt3?/?-catenin/GSK-3? Signaling Pathway to Reduce Renal Fibrosis in Rats with Unilateral Ureteral Obstruction, dissertation, Yanbian University.

Yuan Y, 2022, Study on the Mechanism of Action of Wenyang Zhenshuai Granules on Renal Fibrosis Based on NLRP3 Inflammasome Mediated Pyrodeath, dissertation, Hunan University of Chinese Medicine.

Song G, He J, 2022, Research Progress of SIRT6 and the Mechanism of Diabetic Nephropathy. Chin J Clinical Research, 35(05): 717–720.

Zhou W, 2022, CircPlekha7 Targets miR-493-3p/KLF4 To Inhibit Renal Fibrosis, dissertation, Nanchang University.

Wallace JL, Vaughan D, Dicay M, et al., 2018, Hydrogen Sulfide-Releasing Therapeutics: Translation to the Clinic, Antioxid Redox Signal 28(16): 1533–1540.

Abraham NG, Kappas A, 2008, Pharmacological and Clinical Aspects of Heme Oxygenase. Pharmacol Rev, 60(1): 79–127.

Boczkowski J, Poderoso JJ, Motterlini R, 2006, CO-Metal Interaction: Vital Signaling from a Lethal Gas, Trends Biochem Sci 31(11): 614–621.

Ghosh S, Gal J, Marczin N, 2010, Carbon Monoxide: Endogenous Mediator, Potential Diagnostic and Therapeutic Target, Ann Med 42(1): 1–12.

Shao L, Liu C, Wang S, Liu J, et al., 2018, The Impact of Exogenous CO Releasing Molecule CORM-2 on Inflammation and Signaling of Orthotopic Lung Cancer, Oncol Lett 16(3): 3223–3230.

Zhang W, Tao A, Lan T, et al., 2017, Carbon Monoxide Releasing Molecule-3 Improves Myocardial Function in Mice with Sepsis by Inhibiting NLRP3 Inflammasome Activation in Cardiac Fibroblasts, Basic Res Cardiol, 112(2): 16.

Foresti R, Bani-Hani BG, Motterlini R, 2008, Use of Carbon Monoxide as a Therapeutic Agent: Promises and Challenges, Intensive Care Med, 34(4): 649–658.

Nagao S, Taguchi KH, Sakai R, et al., 2014, Carbon Monoxide-Bound Hemoglobin-Vesicles for the Treatment of Bleomycin-Induced Pulmonary Fibrosis, Biomaterials 35(24): 6553–6562.

Chaves-Ferreira M, Albuquerque IS, Matak-Vinkovic D, et al., 2015, Spontaneous CO Release from Ru(II)(CO)2-Protein Complexes in Aqueous Solution, Cells, and Mice, Angew Chem Int Ed Engl 54(4):1172–1175.

Santos-Silva T, Mukhopadhyay A, Seixas JD, et al., 2011, CORM-3 Reactivity Toward Proteins: The Crystal Structure of a Ru (II) Dicarbonyl-Lysozyme Complex, J Am Chem Soc 133(5): 1192–1195.