Dysbiosis represents changes in composition and structure of the gut microbiome community (microbiome), which may dictate the physiological phenotype (health or disease). Recent technological advances and efforts in metagenomic and metabolomic analyses have led to a dramatical growth in our understanding of microbiome, but still, the mechanisms underlying gut microbiome-host interactions in healthy or diseased state remain elusive and their elucidation is in infancy. Disruption of the normal gut microbiota may lead to intestinal dysbiosis, intestinal barrier dysfunction, and bacterial translocation. Excessive uremic toxins are produced as a result of gut microbiota alteration, including indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide, all implicated in the variant processes of kidney diseases development. This review focuses on the pathogenic association between gut microbiota and kidney diseases (the gut-kidney axis), covering CKD, IgA nephropathy, nephrolithiasis, hypertension, acute kidney injury, hemodialysis and peritoneal dialysis in clinic. Targeted interventions including probiotic, prebiotic and symbiotic measures are discussed for their potential of re-establishing symbiosis, and more effective strategies for the treatment of kidney diseases patients are suggested. The novel insights into the dysbiosis of the gut microbiota in kidney diseases are helpful to develop novel therapeutic strategies for preventing or attenuating kidney diseases and complications.

Fibrosis is a final pathological feature of many chronic diseases, but few interventions are available that specifically target the pathogenesis of fibrosis. The highlights of common cellular and molecular mechanisms of fibrosis facilitate the discovery of effective antifibrotic drugs. The renin-angiotensin system (RAS) plays a central physiological role in the control of blood pressure and fluid homeostasis. Emerging evidence has revealed that activation of RAS was consistently found in fibrotic tissue. At the same time, as more components of the RAS are described, other pot Potential therapeutic targets emerge, so it seems sensible to revisit the contribution of RAS in anti-fibrotic therapy. So far, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are the main commercial available drugs for intervening RAS. However, RAS inhibitors had lots of limitations in long-term application owing to occurring AngII and aldosterone escape. Over the past decades, natural products have aroused growing attention as potential RAS inhibitors due to their high efficacy and low risk of side effects. In this review, we revisit the contribution of RAS and its new members to anti-fibrotic therapy. Ultimately, we summarize and evaluate the use of natural products including isolated compounds, crude extracts and traditional Chinese herbal formulas to regulate RAS. These natural products can retard tissue fibrosis by targeting different RAS components, which provide us new therapeutic strategies to discover anti-fibrotic drugs.

Kidney diseases are serious public problems with high morbidity and mortality in the general population and heavily retard renal function with aging regardless of the cause. Although myriad strategies have been assigned to prevent or harness disease progression, unfortunately, thus far, there is a paucity of effective therapies partly due to an insufficient knowledge of underlying pathological mechanisms, indicating deeper studies are urgently needed. Additionally, natural products are increasingly recognized as an alternative source for disease intervention owing to the potent safety and efficacy, which might be exploited for novel drug discovery. In this review, we primarily expatiate the new advances on mediators that might be amenable to targeting aging kidney and kidney diseases, including nicotinamide adenine dinucleotide phosphate oxidase (NOX), transforming growth factor-β (TGF-β), renin-angiotensin system (RAS), nuclear factor-erythroid 2 related factor 2 (Nrf2), peroxisome proliferator-activated γ receptor (PPARγ), advanced glycation endproducts (AGEs) as well as microRNAs and vitagenes. Of note, we conclude by highlighting some natural products which have the potential to facilitate the development of novel treatment for patients with myriad renal diseases.

Background

Increasing evidence suggests a link between the gut microbiome and various diseases including hypertension and chronic kidney disease (CKD). However, studies examining the efficacy of controlling blood pressure and inhibiting the renin-angiotensin system (RAS) in preventing CKD progression are limited.

Methods

In the present study, we used 5/6 nephrectomised (NX) and unilateral ureteral obstructed (UUO) rat models and cultured renal tubular epithelial cells and fibroblasts to test whether alisol B 23-acetate (ABA) can attenuate renal fibrogenesis by regulating blood pressure and inhibiting RAS.

Results

ABA treatment re-established dysbiosis of the gut microbiome, lowered blood pressure, reduced serum creatinine and proteinuria, suppressed expression of RAS constituents and inhibited the epithelial-to-mesenchymal transition in NX rats. Similarly, ABA treatment inhibited expression of collagen I, fibronectin, vimentin, α-smooth muscle actin and fibroblast-specific protein 1 at both mRNA and protein levels in UUO rats. ABA was also effective in suppressing activation of the transforming growth factor-β (TGF-β)/Smad3 and preserving Smad7 expression in both NX and UUO rats. In vitro experiments demonstrated that ABA treatment inhibited the Wnt/β-catenin and mitochondrial-associated caspase pathways.

Conclusion

These data suggest that ABA attenuated renal fibrosis through a mechanism associated with re-establishing dysbiosis of the gut microbiome and regulating blood pressure, and Smad7-mediated inhibition of Smad3 phosphorylation. Thus, we demonstrate ABA as a promising candidate for treatment of CKD by improving the gut microbiome and regulating blood pressure.

Background and purpose

Increasing evidence has indicated that the high risk of cardiovascular disease in chronic kidney disease (CKD) patients cannot be sufficiently explained by classic risk factors.

Experimental approach

Based on the least absolute shrinkage and selection operator method, we identified significantly altered renal tissue metabolites during progressive CKD in a 5/6 nephrectomized rat model and in CKD patients.

Key results

Six aryl-containing metabolites (ACMs) were significantly increased from Week 1 to Week 20. They were associated with the activation of aryl hydrocarbon receptor (AhR) and its target genes including CYP1A1, CYP1A2 and CYP1B1, which were further validated by molecular docking. Our study further demonstrated that AhR signalling could be activated by ACM in patients with idiopathic membranous nephropathy, diabetic nephropathy and IgA nephropathy. Most importantly, 1-aminopyrene (AP) showed strong positive and negative correlation with serum creatinine and creatinine clearance, respectively. AP significantly up-regulated the mRNA expressions of AhR and its three target genes in both mice and NRK-52E cells, while this effect was partially weakened in AhR small hairpin RNA-treated mice and NRK-52E cells. Furthermore, dietary flavonoid supplementation ameliorated CKD and renal fibrosis through partially inhibiting the AhR activity via lowering the ACM levels. The antagonistic effect of flavonoids on AhR was deeply influenced by the number and location of hydroxyl and glycosyl groups.

Conclusion and implications

We uncovered that endogenous AP is a novel mediator of CKD progression via AhR activation; thus, AhR might serve as a promising target for CKD treatment.