The effect of dicarbonyl stress on the development of kidney dysfunction in metabolic syndrome – a transcriptomic and proteomic approach

Abstract

Background and aims Dicarbonyl stress plays an important role in the pathogenesis of microvascular complications that precede the formation of advanced glycation end products, and contributes to the development of renal dysfunction. In renal cells, toxic metabolites like methylglyoxal lead to mitochondrial dysfunction and protein structure modifications. In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in the model of metabolic syndrome. Materials and methods Dicarbonyl stress was induced by intragastric administration of methylglyoxal (0.5 mg/kg bw for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats with insulin resistance and fatty liver. Results Methylglyoxal administration aggravated glucose intolerance (AUC 0–120 p < 0.05), and increased plasma glucose ( p < 0.01) and insulin ( p < 0.05). Compared to controls, methylglyoxal-treated rats exhibited microalbuminuria ( p < 0.01). Targeted proteomic analysis revealed increases in urinary secretion of pro-inflammatory parameters (MCP-1, IL-6, IL-8), specific collagen IV fragments and extracellular matrix proteins. Urine metabolomic biomarkers in methylglyoxal-treated rats were mainly associated with impairment of membrane phospholipids (8-isoprostane, 4-hydroxynonenal). Decreased levels of glutathione ( p < 0.01) together with diminished activity of glutathione-dependent antioxidant enzymes contributed to oxidative and dicarbonyl stress. Methylglyoxal administration elevated glyoxalase 1 expression ( p < 0.05), involved in methylglyoxal degradation. Based on comparative transcriptomic analysis of the kidney cortex, 96 genes were identified as differentially expressed (FDR < 0.05). Network analysis revealed an over-representation of genes related to oxidative stress and pro-inflammatory signalling pathways as well as an inhibition of angiogenesis suggesting its contribution to renal fibrosis. Conclusion Our results support the hypothesis that dicarbonyl stress plays a key role in renal microvascular complications. At the transcriptome level, methylglyoxal activated oxidative and pro-inflammatory pathways and inhibited angiogenesis. These effects were further supported by the results of urinary proteomic and metabolomic analyses.

Adverse Effects of Methylglyoxal on Transcriptome and Metabolic Changes in Visceral Adipose Tissue in a Prediabetic Rat Model

“…Upregulated Lpin1 positively affects triglyceride biosynthesis control in the endoplasmic reticulum, while Nr1d1 regulates lipid metabolism by influencing SREBPs and PPARα. On the other hand, downregulated Lrpap1 , which encodes a protein that interacts with LDL receptors, is involved in the alteration of circulating lipids, as observed after MG exposure in our study [ 18 ] and in others [ 4 , 5 ].…”

“…However, serum adiponectin levels ( Table 1 ) and skeletal muscle insulin sensitivity (data not shown) in MG-treated rats were not different to controls. While MG administration increased adrenaline-stimulated lipolysis ( Figure 1 B), NEFA concentrations only increased slightly [ 18 ].…”

“…Although MG administration had no effect on circulating triglyceride or ectopic triglyceride accumulation [ 18 ], transcriptome analysis did reveal the involvement of MG in the regulation of adipose tissue lipid metabolism. Upregulated Lpin1 positively affects triglyceride biosynthesis control in the endoplasmic reticulum, while Nr1d1 regulates lipid metabolism by influencing SREBPs and PPARα.…”

Downregulation of the Glo1 Gene Is Associated with Reduced Adiposity and Ectopic Fat Accumulation in Spontaneously Hypertensive Rats

“…It has been reported that MG treatment inhibited the insulin receptor pathway in 3T3L1 adipocytes [30,31] and pancreatic cell line INS-1E [32]. One study to treat hereditary hypertriglyceridemic rats (a model of dyslipidemia and insulin resistance) with intragastric administration of MG (0.5 mg/kg body weight for 4 weeks) reported a development in dicarbonyl and oxidative stress associated with reduced glucose tolerance and renal microvascular complications [33]. Another study showed that Sprague-Dawley rats treated with 1% MG in drinking water for 4 weeks were predisposed to diabetes and salt-sensitive hypertension [34].…”

In vivo AAV delivery of glutathione reductase gene attenuates anti-aging gene klotho deficiency-induced kidney damage

“…To confirm the anti-oxidative effect of AAV-GR in kidney, we monitored urinary 8-isoprostane concentration, another marker of renal oxidative stress [ [30] , [31] , [32] , [33] ], at different time points after AAV-GR delivery. A significantly higher urinary level of 8-isoprostane was found in KL +/– mice versus WT mice ( Fig.…”