Natural Products in Renal-Associated Drug Discovery

Abstract

The global increase in the incidence of kidney failure constitutes a major public health problem. Kidney disease is classified into acute and chronic: acute kidney injury (AKI) is associated with an abrupt decline in kidney function and chronic kidney disease (CKD) with chronic renal failure for more than three months. Although both kidney syndromes are multifactorial, inflammation and oxidative stress play major roles in the diversity of processes leading to these kidney malfunctions. Here, we reviewed various publications on medicinal plants with antioxidant and anti-inflammatory properties with the potential to treat and manage kidney-associated diseases in rodent models. Additionally, we conducted a meta-analysis to identify gene signatures and associated biological processes perturbed in human and mouse cells treated with antioxidants such as epigallocatechin gallate (EGCG), the active ingredient in green tea, and the mushroom Ganoderma lucidum (GL) and in kidney disease rodent models. We identified EGCG- and GL-regulated gene signatures linked to metabolism; inflammation (NRG1, E2F1, NFKB1 and JUN); ion signalling; transport; renal processes (SLC12A1 and LOX) and VEGF, ERBB and BDNF signalling. Medicinal plant extracts are proving to be effective for the prevention, management and treatment of kidney-associated diseases; however, more detailed characterisations of their targets are needed to enable more trust in their application in the management of kidney-associated diseases.

Keywords: AKI; CKD; anti-inflammatory; antioxidant; natural medicinal products.

Figure 1

Gene signature upregulated by EGCG. (A) Venn diagram comparison of genes upregulated in EGCG-treated human skin cells, human T cells and mouse colon cells. The orange circle marks the 11 genes upregulated in common in all 3 datasets, and the red ellipse marks the 23 (11 + 12) genes upregulated in common in the two human datasets. (B) Overrepresented GO terms in the common signatures of the 11 genes. (C) Overrepresented GO terms in the common human EGCG signatures of the 23 genes. The large overlap between both GO analysis results shows that most of these biological processes are conserved between men and mice. The results can be grouped into metabolic (amine and phenol metabolism), ion transport, membrane and secretory categories. (D) The EGCG gene signatures from the marked subsets of the Venn diagram.

Figure 2

Gene signature downregulated by EGCG. (A) Venn diagram comparison of the genes downregulated in EGCG-treated human skin cells, human T cells and mouse colon cells. The orange circle marks the 13 genes downregulated in common in all 3 datasets, and the red ellipse marks the 50 (13 + 37) genes downregulated in common in the two human datasets. (B) Overrepresented GO terms in the common signatures of the 13 genes. (C) Overrepresented GO terms in the common human EGCG signatures of the 50 genes. The large overlap between both GO analysis results shows that most of these biological processes are conserved between men and mice. The results can be grouped into calcium signalling, neuronal and synaptic, inflammatory (response to wounding), connective tissue, ion transport and taxis categories. (D) The EGCG gene signatures from the marked subsets of the Venn diagram.

Figure 3

EGCG-associated gene signatures may have an impact on the kidneys and are associated with inflammatory processes regulated by the transcription factors NFKB1, JUN and E2F1. (A) The enrichment analysis results of the EGCG-downregulated 50 (13 + 37) genes in the UK_Biobank_GWAS_v1 dataset collection and (B) the “Jensen Diseases” dataset collection. (C) Most EGCG-downregulated genes are regulated by transcription factor E2F1. (D) Most EGCG-upregulated genes are regulated by transcription factors JUN and NFKB1. (E) Protein interaction network of E2F1, NFKB1 and JUN expanded by five interacting proteins made via STRING-DB. (F) Top 20 Reactome pathways found by STRING-SB in the network of (E) reveal inflammatory processes. (G) Top 20 WikiPathway pathways found by STRING-SB in the network of (E) neuroinflammation and other inflammatory processes.

Figure 4

EGCG-associated gene signatures are transferred to kidney datasets with other antioxidant compounds. (A) Venn diagram comparison of the human skin and T-cell up- and downregulated EGCG gene signatures to dataset GSE198890 of HEK cells treated with VT01454 shows only 1+1 genes overlapping. (B) In dataset GSE159656 of Galoderma lucidum-treated mouse kidney cells, there is more overlap of the indicated six genes in the downregulated EGCG signature and two genes in the upregulated EGCG signature. (C) The six EGCG-downregulated genes overlapping can be further characterised by the overrepresented renal impairment processes found by the R package EnrichR; however, they are only associated with single genes: SLC12A1 or LOX.

Figure 5

Ganoderma lucidum-associated gene signatures are compared to kidney datasets with PAN and ANGII stimulation. (A) Venn diagram comparison of up- and downregulated genes in Ganoderma lucidum (GL)-treated mouse kidney and PAN-treated human kidney organoids. (B) Venn diagram comparison of up- and downregulated genes in GL-treated mouse kidney and ANGII-treated human urine-derived podocytes. The dot plots in (C–F) show the most significant overrepresented GO terms in the Venn diagram subsets with matching colours. (C) The most significant GO terms in the 100 genes upregulated in GL and downregulated in PAN include VEGF signalling. (D) The most significant GO terms in the 36 genes downregulated in GL and downregulated in PAN include sterol synthesis and blood circulation/pressure. (E) The most significant GO terms in the 90 genes upregulated in GL and downregulated in ANGII include epithelial cell development, inflammatory processes such as interferon-alpha and leukaemia inhibitory factor responses and ERBB and BDNF signalling. (F) The most significant GO terms in the 76 genes upregulated in GL and upregulated in ANGII include ADP synthesis and metabolism and several other metabolic processes, as well as the positive regulation of acute inflammatory processes.