Nanoparticle-Mediated Delivery of Emodin via Colonic Irrigation Attenuates Renal Injury in 5/6 Nephrectomized Rats

Abstract

Our previous study showed that emodin enema modulates gut microbiota and delays CKD progression. However, the poor solubility, limited colonic irrigation retention time, and inadequate colon adhesion of emodin hinder its clinical application. Based on the deficiencies of emodin, we prepared monomethoxy-poly (ethylene glycol)-poly (lactic acid)-chitosan-2-mercaptobenzimidazole nanoparticles with incorporated emodin (emodin-NP) and studied their efficacy in delaying CKD progression. 5/6 nephrectomized Male Sprague Dawley rats were administered via colonic irrigation with emodin-NP every two days for eight weeks. We found that treatment with emodin-NP improved the kidney function of the rats and limited the expansion of tubulointerstitial fibrosis. Treatment with emodin-NP once every two days is comparable to emodin treatment once a day. Furthermore, emodin-NP via colonic irrigation remarkably reduced IL-1β, IL-6, and LPS levels in serum, improved intestinal barrier functions, and downregulated the key proteins (TLR4, MyD88, and NF-κB) expression in intestinal TLR4 signaling pathway. 16S rDNA analyses showed that emodin-NP can regulate microbiota disturbance in CKD. Taken together, these results suggest that emodin-NP alleviates kidney dysfunction and tubulointerstitial fibrosis by mediation through the modification of gut microbiota disorders. Emodin-NP may be a new method to treat CKD.

The modulation of gut microbiota by herbal medicine to alleviate diabetic kidney disease – A review

“…In addition, the increased abundance of Lactobacillus and Akkermansia, which serve as lactic and butyric acid-producing probiotics, respectively, can alleviate renal fibrosis by modulating bacterial metabolites to ameliorate renal inflammation, reduce uremic toxins production, and restore the intestinal barrier (Belzer et al, 2017;Lopes et al, 2018). Furthermore, similar results were obtained in cyclosporin A-induced mice that received fecal transplantation from Astragalus mongholicus Bunge and Salvia miltiorrhiza Bunge-treated mice (Han et al, 2021).…”

“…Rheum palmatum L. can also decrease the abundance of conditionally pathogenic microbes such as Alcaligenaceae, Methanosphaera, and Clostridiaceae in the intestine of 5/6 Nephrectomy rats compared to the CKD model, restoring the functions of the intestinal barrier and alleviating renal fibrosis (Ji et al, 2020). Ji et al (Ji et al, 2021)further investigated the relationship between Rheum palmatum L. enema and TMAO. 5/6 Nephrectomy rats were divided into the model group, Rheum palmatum L. high-dose group (2.10 g/kg/day), and Rheum palmatum L. low-dose group (1.05 g/kg/day).…”

“…As a combination, they can alleviate kidney damage and protect kidney functions in the treatment of CKD (Huang et al, 2018). Studies have found that the combination of Astragalus mongholicus Bunge and Salvia miltiorrhiza Bunge (2: 1, 8.4 g/kg/d) restored the abundance and diversity of intestinal flora in cyclosporin A-induced mice and modified the ratio of Firmicutes to Bacteroidetes (F/B), thereby attenuating the disorder of intestinal flora to some extent (Han et al, 2021). In addition, the increased abundance of Lactobacillus and Akkermansia, which serve as lactic and butyric acid-producing probiotics, respectively, can alleviate renal fibrosis by modulating bacterial metabolites to ameliorate renal inflammation, reduce uremic toxins production, and restore the intestinal barrier (Belzer et al, 2017;Lopes et al, 2018).…”

Network Pharmacology and In Vivo Analysis of Dahuang-Huangqi Decoction Effectiveness in Alleviating Renal Interstitial Fibrosis

“…Previous reports have presented that rhein may decrease interstitial fibrosis through antioxidants via activating the SIRT3/FOXO3a signaling pathway [ 33 ]. Research suggests that emodin alleviates kidney dysfunction and tubulointerstitial fibrosis through the modification of gut microbiota disorders and via remarkably reduced IL-6 levels in serum, improved intestinal barrier functions, and downregulated key proteins (TLR4 and NF- κ B) expression in the intestinal TLR4 signaling pathway [ 34 ]. Peng et al observed that gallic acid is renal protective in the long-term treatment of CKD via the PI3K/AKT signaling pathway [ 35 ].…”

Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways

“…Similarly, a number of publications have demonstrated that emodin retarded renal fibrosis by modulating several pathways, such as TGF-β/Smad, TGF-β/BMP-7, PI3K/Akt/GSK-3β, and Bax/caspase-3 signaling pathways ( Jing et al, 2017 ; Ma et al, 2018b ; Yang et al, 2020 ; Liu et al, 2021c ). Furthermore, several studies have demonstrated the inhibitory effect of emodin on renal fibrosis by suppressing the NF-ƙB p65 protein expression ( Lu et al, 2020 ) or the levels of ROS, TNF-α, and interleukin-6 ( Chen et al, 2017c ; Jing et al, 2017 ). So far, no publication demonstrated the renoprotective effect of chrysophanol through modulating the IƙB/NF-ƙB signaling pathway.…”