Carnosic Acid Attenuates Cadmium Induced Nephrotoxicity by Inhibiting Oxidative Stress, Promoting Nrf2/HO-1 Signalling and Impairing TGF-β1/Smad/Collagen IV Signalling.

Abstract

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05-0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-β1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity.

• Authors: Sonjit Das, Saikat Dewanjee, Tarun K Dua, Swarnalata Joardar, Pratik Chakraborty, Shovonlal Bhowmick, Achintya Saha, Simanta Bhattacharjee, Vincenzo De Feo
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 22 (Nov 18 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 31752142 (Publication Type: Journal Article)

Chemical References

• Abietanes
• Antioxidants
• Collagen Type IV
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Smad Proteins
• TGFB1 protein, human
• Transforming Growth Factor beta1
• Cadmium
• Heme Oxygenase-1
• Cadmium Chloride
• salvin

Topics

• Abietanes (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Cadmium (pharmacology)
• Cadmium Chloride (antagonists & inhibitors, toxicity)
• Cell Line
• Collagen Type IV (metabolism)
• Heme Oxygenase-1 (metabolism)
• Kidney (drug effects, metabolism, pathology)
• Mice
• Molecular Docking Simulation
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• Signal Transduction (drug effects)
• Smad Proteins (metabolism)
• Transforming Growth Factor beta1 (metabolism)