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. 2022 Jun 16:13:891788.
doi: 10.3389/fphar.2022.891788. eCollection 2022.

Phyllanthus Niruri L. Exerts Protective Effects Against the Calcium Oxalate-Induced Renal Injury via Ellgic Acid

Mao-Ting Li  1 , Lu-Lu Liu  1 , Qi Zhou  1 , Lin-Xi Huang  1 , Yu-Xuan Shi  1 , Jie-Bin Hou  2 , Hong-Tao Lu  3 , Bing Yu  4 , Wei Chen  1 , Zhi-Yong Guo  1
Affiliations

Phyllanthus Niruri L. Exerts Protective Effects Against the Calcium Oxalate-Induced Renal Injury via Ellgic Acid

Mao-Ting Li et al. Front Pharmacol. .

Erratum in

Abstract

Background: Urolithiasis or kidney stones is a common and frequently occurring renal disease; calcium oxalate (CaOx) crystals are responsible for 80% of urolithiasis cases. Phyllanthus niruri L. (PN) has been used to treat urolithiasis. This study aimed to determine the potential protective effects and molecular mechanism of PN on calcium oxalate-induced renal injury. Methods: Microarray data sets were generated from the calcium oxalate-induced renal injury model of HK-2 cells and potential disease-related targets were identified. Network pharmacology was employed to identify drug-related targets of PN and construct the active ingredient-target network. Finally, the putative therapeutic targets and active ingredients of PN were verified in vitro and in vivo. Results: A total of 20 active ingredients in PN, 2,428 drug-related targets, and 127 disease-related targets were identified. According to network pharmacology analysis, HMGCS1, SQLE, and SCD were identified as predicted therapeutic target and ellagic acid (EA) was identified as the active ingredient by molecular docking analysis. The increased expression of SQLE, SCD, and HMGCS1 due to calcium oxalate-induced renal injury in HK-2 cells was found to be significantly inhibited by EA. Immunohistochemical in mice also showed that the levels of SQLE, SCD, and HMGCS1 were remarkably restored after EA treatment. Conclusion: EA is the active ingredient in PN responsible for its protective effects against CaOx-induced renal injury. SQLE, SCD, and HMGCS1 are putative therapeutic targets of EA.

Keywords: Phyllanthus niruri L.; calcium oxalate-induced renal injury; ellagic acid; lipid nephrotoxicity; network pharmacology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Hub ingredients and targets screening (A) An ingredient-target network and nodes represent ingredients (red) and targets form STITCH (blue), Pharmmapper (green) or both (orange) (B) Heatmap of potential disease-related targets on microarray analysis between HK-2 cells cultured with (NaOx group) or without (Ctrl group) NaOx (C) Venn diagram showing the overlap of diease-related (Oxalate-induced renal injury related) targets (blue) and drug-related (Phyllanthus niruri. L related) targets (green) (D) The active ingredient-predicted therapeutic target network.
FIGURE 2
FIGURE 2
Molecular docking. Three-dimensional (left) and two-dimensional (right) ligand interaction diagrams of ellagic acid and the original ligands of HMGCS1 (A), SCD (B), and SQLE (C).
FIGURE 3
FIGURE 3
The changing trend of SQLE, HMGCS1, and SCD in oxalate-induced renal injury models (A) The Heatmap of SQLE, HMGCS1and SCD were shown in three GSE databases (B) Expression of SQLE, HMGCS1 and SCD protein was detected by Western blot in the sodium oxalate group (NaOx) at 0, 12, and 24 h (C) Western blot displayed as column charts after quantification.
FIGURE 4
FIGURE 4
Ellagic acid protects NaOx-induced injury in cells and reduces the expression of SQLE, HMGCS1, and SCD (A) The cytotoxicity of ellagic acid on HK-2 cells determined by the CCK8 assay (B) The cytotoxicity of ellagic acid on NaOx treated HK-2 cells determined by the CCK8 assay (C) The expression of SQLE, HMGCS1, and SCD by Western blot in the control group (Ctrl), sodium oxalate group (NaOx), and ellagic acid treatment group (NaOx + EA) (D) Cells were analyzed by immunocytochemistry (100X) in the control group (Ctrl), sodium oxalate group (NaOx), and ellagic acid treatment group (NaOx + EA).
FIGURE 5
FIGURE 5
Ellagic acid protects calcium oxalate-induced renal injury in mice and reduces the expression of SQLE, HMGCS1, and SCD (A) Representative light microscopy images of hematoxylin and eosin staining of kidneys from the control group (Con), glyoxylate-induced CaOx group (Gly), and ellagic acid treatment group (Gly + EA) (magnification, ×200; scale bar = 50 μm) (B) Serum creatinine level in control group (Con), glyoxylate-induced CaOx group (Gly), and ellagic acid treatment group (Gly + EA) (C) The GPx activities, MDA, and total calcium content in control group (Con), glyoxylate-induced CaOx group (Gly), and ellagic acid treatment group (Gly + EA) (D) Expression of SCD, HMGCS1, and SQLE were analyzed by immunohistochemistry (IHC) (left) Representative light microscopy images of IHC staining of kidney of mice (magnification, ×200; scale bar = 50 μm (up) and 25 μm (down)); (right) Semi-quantitative score of SCD, HMGCS1, and SQLE.
FIGURE 6
FIGURE 6
Ellagic acid reduces the expression of p53 (A) Expression of p53 protein was detected by western blot in the sodium oxalate group (NaOx) at 0, 12, and 24 h (B) Expression of p53 protein was detected by Western blot in the ellagic acid treatment group (NaOx + EA) at 0, 12, and 24 h (C) Two-dimensional (left) and three-dimensional (right) ligand interaction diagrams of ellagic acid and the original ligands of p53.
FIGURE 7
FIGURE 7
Diagram of the putative regulatory mechanisms of the ellagic acid.
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