Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis.

AIMS: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, has received extensive attention as a natural activator of the Nrf2/Keap1 cytoprotective pathway. In this review, a meta-analysis and systematic review of the renoprotective effects of SFN were performed in various preclinical models of kidney diseases. MAIN METHODS: The primary outcome was the impact of SFN on renal function biomarkers (uremia, creatininemia, proteinuria or creatinine clearance) and secondary outcomes were kidney lesion histological indices/kidney injury molecular biomarkers. The effects of SFN were evaluated according to the standardized mean differences (SMDs). A random-effects model was applied to estimate the overall summary effect. KEY FINDINGS: Twenty-five articles (out of 209 studies) were selected from the literature. SFN administration significantly increased creatinine clearance (SMD +1.88 95 % CI: [1.09; 2.68], P < 0.0001, I2 = 0 %) and decreased the plasma creatinine (SMD -1.24, [-1.59; -0.88], P < 0.0001, I2 = 36.0 %) and urea (SMD -3.22 [-4.42, -2.01], P < 0.0001, I2 = 72.4 %) levels. SFN administration (median dose: 2.5 mg/kg, median duration: 3 weeks) significantly decreased urinary protein excretion (SMD -2.20 [-2.68; -1.73], P < 0.0001, I2 = 34.1 %). It further improved two kidney lesion histological indices namely kidney fibrosis (SMD -3.08 [-4.53; -1.63], P < 0.0001, I2 = 73.7 %) and glomerulosclerosis (SMD -2.24 [-2.96; -1.53], P < 0.0001, I2 = 9.7 %) and decreased kidney injury molecular biomarkers (SMD -1.51 [-2.00; -1.02], P < 0.0001, I2 = 0 %). SIGNIFICANCE: These findings provide new insights concerning preclinical strategies for treating kidney disease or kidney failure with SFN supplements and should stimulate interest in clinical evaluations of SFN in patients with kidney disease.

From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF-κB/Nrf2 expression.

PURPOSE: Uremic toxins produced by gut microbiota (indoxyl sulfate-IS, p-cresyl sulfate-p-CS, and indole-3-acetic acid-IAA) accumulate in hemodialysis (HD) patients and exhibit potent inflammatory effects. However, the impact of these toxins on nuclear E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) expression in HD patients remains poorly defined. The aim of this study was to evaluate the association between uremic toxins and Nrf2/NF-κB expression in vitro (RAW 264.7 macrophage-like cells) and in peripheral blood mononuclear cells from HD patients. METHODS: Uremic toxins, C-reactive protein (CRP), interleukin-6 (IL-6) and malondialdehyde (MDA) levels were measured in fifteen HD patients and nine healthy individuals. RAW 264.7 macrophage-like cells were incubated with IS, as a prototype of protein-bound uremic toxin. Nrf2 and NF-κB expressions were analyzed by RT-qPCR. RESULTS: HD patients presented high levels of inflammatory markers, MDA and uremic toxins. In addition, they presented high NF-κB and low Nrf2 expression. Uremic toxins were positively correlated with NF-κB expression (IS, ρ = 0.58, p < 0.003; p-CS, ρ = 0.71, p < 0.001; IAA, ρ = 0.62, p < 0.001) and negatively with Nrf2 (IS, ρ = - 0.48, p = 0.01; p-CS, ρ = - 0.46, p < 0.02). Uremic toxins also exhibited positive correlations with CRP and MDA levels. Multivariate analysis revealed that p-CS is a determinant factor of NF-κB expression. In RAW 264.7 culture, NF-κB mRNA expression was stimulated by IS, while Nrf2 was downregulated. CONCLUSIONS: Thus, uremic toxins may stimulate NF-κB mRNA and decrease Nrf2 expression in HD patients and, consequently, trigger inflammation and oxidative stress.

Aryl Hydrocarbon Receptor Activation in Chronic Kidney Disease: Role of Uremic Toxins.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the expression of xenobiotic-metabolizing enzymes, inflammatory cytokines and adhesion molecules. Uremic toxins such as indoxyl sulfate and indole acetic acid are derived from tryptophan fermentation by gut microbiota; they accumulate in patients with chronic kidney disease (CKD) on haemodialysis and have recently emerged as potent ligands of AhR. Therefore, AhR can serve as a mediator in inflammation and cardiovascular diseases in these patients. This review discusses current data that support a link between AhR activation and uremic toxins from gut microbiota in CKD.

Determination of the binding properties of the uremic toxin phenylacetic acid to human serum albumin.

Uremic toxins are compounds normally excreted in urine that accumulate in patients with chronic kidney disease as a result of decreased renal clearance. Phenylacetic acid (PAA) has been identified as a new protein bound uremic toxin. The purpose of this study was to investigate in vitro the interaction between PAA and human serum albumin (HSA) at physiological and pathological concentrations. We used ultrafiltration to show that there is a single high-affinity binding site for PAA on HSA, with a binding constant on the order of 3.4 × 10(4) M(-1) and a maximal stoichiometry of 1.61 mol per mole. The PAA, at the concentration reported in end-stage renal patients, was 26% bound to albumin. Fluorescent probe competition experiments demonstrated that PAA did not bind to Sudlow's site I (in subdomain IIA) and only weakly bind to Sudlow's site II (in subdomain IIIA). The PAA showed no competition with other protein-bound uremic toxins such as p-cresyl-sulfate or indoxyl sulfate for binding to serum albumin. Our results provide evidence that human serum albumin can act as carrier protein for phenylacetic acid.