C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

Abstract

Aims/hypothesis Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. Methods Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). Results Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. Conclusions/interpretation The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

“…once every day, for five consecutive days. 17,18 Fasting glucose levels (4-hour fast) were determined 1 week after the last injection. Mice with fasting glucose levels above 13.89 mmol/L were considered diabetic.…”

The Use of Natural Products in the Management of Diabetes: The Current Trends

“…Furthermore, curcumin exhibits a poor bioavailability in plasma and in target tissues, which may hinder its therapeutic efficacy [35] . Therefore, the improvement of the pharmacokinetics and the increase in the plasma concentration of curcumin are significant therapeutic targets in the application of curcumin for the treatment of DCM.…”

“…Therefore, the improvement of the pharmacokinetics and the increase in the plasma concentration of curcumin are significant therapeutic targets in the application of curcumin for the treatment of DCM. Recently, C66, a curcumin derivative with much a higher bioavailability [35,36] , (Wu, et al, 2016;Pan, et al, 2014), was found to activate Nrf2 and its downstream antioxidants in the kidneys and aortas of the STZ-induced diabetic mice [35,37] . Nrf2 played a prominent role in the C66 protection against diabetic nephropathy, since C66 lost partial, but significant, protection against the DM-induced renal damage [35] in the Nrf2 knockout mice.…”

Effects of Curcumin in Experimental Diabetic Nephropathy

“…Other recent investigations focused on the inhibitory effects of curcumin on microRNA, especially miR-124 on podocytes, to explain the renoprotective effects in DN 49. Wu et al 50 showed that C66 contributes to renal protection by upregulation of NRF2 by activating miR200 and inhibiting miR21. Interestingly, some investigators have linked the renal effects of curcumin to prevention of epithelial-mesenchymal transformation (EMT) as a result of activation of NRF2 and heme oxygenase-151 or by suppressing the phosphorylation of cav-1 and increasing the stabilization of cav-1 and β-catenin 52.…”