Rhein lysinate protects renal function in diabetic nephropathy of KK/HlJ mice

Abstract

The purpose of the present study was to assess the protective effects of rhein lysinate (RHL) in a KK/HlJ mouse model of diabetic nephropathy (DN) and to explore its mechanism of action. A total of 4 groups were established: C57BL/J control, the KK/HlJ model and 25 and 50 mg/kg/day RHL-treated KK/HlJ groups. The KK/HlJ mouse model of DN was established by streptozotocin injection, followed by maintenance on a specific diet. The albumin-to-creatinine ratio (ACR) was determined at 5 weeks and at 16 weeks, the kidneys were harvested, and morphological examination and immunohistochemical analysis were performed. The levels of malondialdehyde (MDA), as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities in the kidneys were measured using appropriate assay kits. The expression of inflammatory factors and associated proteins was analyzed using western blot analysis. At 5 weeks, the levels of ACR in KK/HlJ mice were increased, which was inhibited by treatment with RHL. Treatment with RHL (50 mg/kg/day) decreased the body weight of KK/HlJ mice. Compared with the C57BL/J control, the KK/HlJ model mice had a significantly lower activity of SOD and GSH-px in the kidneys, but had significantly higher levels of MDA. Treatment of KK/HlJ mice with RHL significantly increased the activities SOD and GSH-px, and reduced the MAD level in the kidneys. Renal tubular epithelial cell edema was observed in KK/HlJ mice but not in C57BL/J mice. RHL decreased the incidence of renal tubular epithelial cell edema and significantly decreased the expression of TNF-α and IL-6 as well as the expression and phosphorylation of NF-κB in the kidneys. Therefore, DN is associated with the expression of inflammatory factors, renal tubular epithelial cell edema and renal dysfunction in KK/HlJ mice. RHL improves renal function by decreasing kidney inflammation.

A Significant Association Between Rhein and Diabetic Nephropathy in Animals: A Systematic Review and Meta-Analysis

“…Oxidative stress is of great effect for the occurrence and development of DN, while SOD and MDA are common indicators of oxidative stress. Lin et al (2017) indicated that rhein increased the level of SOD and decreased the level of MDA in kidney tissues of KK/HlJ mice. (Li and Zhen, 2017) found that medium-dose rhein had stronger effect on ameliorating SOD and MDA than low-dose.…”

“…There was significant association of rhein with TGF-β 1 (n = 34, SMD = -1.49, 95%CI [-2.28, -0.71], P = 0.0002; Heterogeneity: Chi² = 0.00, P = 0.99, I² = 0% Figure 10). There were no data on blood glucose, MDA and SOD in these studies listed as follows: Duan et al, 2015;Gao et al, 2010;Wu, 2015;Lin et al, 2017, but blood glucose, MDA and SOD were presented graphically. These studies were not included in quantitative analyses, but all reported that rhein had significant effects on blood glucose (P < 0.05), MDA (P < 0.05) and SOD (P < 0.05).…”

“…Fifteen studies (60%) selected short duration and 8 studies (32%) used long duration, the rest studies included both long and short course. The characteristics of the 25 included studies were shown in Table 1 (Guo et al, 2002;Zhu et al, 2002;Ai et al, 2004;Huang et al, 2004;Zhang et al, 2005;Gong et al, 2006;Jia et al, 2007;Liu and Ning, 2007;Jin et al, 2008;Li 2008;Gao et al, 2010;Li and Yang, 2010;Wang et al, 2011;Huang et al, 2012;Wang et al, 2012;Chen et al, 2013;Hu et al, 2014;Chen et al, 2015a;Chen et al, 2015b;Duan et al, 2015;Wu 2015;Li and Zhen, 2017;Lin et al, 2017;Qiao et al, 2017;.…”

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

“…Thus, at least part of the nephroprotective effect of BMP7 administration in diverse models of kidney fibrosis, including streptozotocin-induced DKD, was mediated by restoring TET3 mRNA expression and protein levels suppressed by TGF-β1, resulting in TET3-mediated restoration of the expression of the antifibrotic gene Rasal1. In this regard, aberrant Rasal1 methylation and hydroxymethylation were corrected by BMP7 [82] which is a nephroprotective compound for different models of CKD, including diabetic nephropathy (DN) [83]. A potential mechanism of kidney protection may be the recovery of Klotho expression by reducing the characteristic Klotho promoter hypermethylation, which is observed in CKD [84].…”

Functional Metabolomics Analysis Elucidating the Metabolic Biomarker and Key Pathway Change Associated With the Chronic Glomerulonephritis and Revealing Action Mechanism of Rhein

“…Modern pharmacology studies have showed that RH could obviously restrains the proliferation of glomerular mesangial cells and hypertrophy of glomerulus, the production and accumulation of extracellular matrix. In addition, it suppresses mRNA transcription, thrombospondin-1 (TSP-1), and transforming growth factor-beta1 (TGF-β1) expression in renal tubular epithelial cells in order to reduce urinary protein and renal fibrosis, ameliorate renal function to protect against CGN deterioration mediated by regulating MAPK signaling pathway, PI3K-AKT signaling pathway, TGF-β signaling pathway, Wnt signaling pathway, VEGF signaling pathway, and others ( Zheng et al., 2008 ; He et al., 2011 ; Zeng et al., 2014 ; Lian et al., 2014 ; Lin et al., 2017 ; Wang et al., 2018 ). It is easy to see that RH protects against CGN in multi-target and multi-level way.…”