Introduction: The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome-the hereditary hypertriglyceridemic rat (HHTg)-by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age. Results: Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%, P < 0.01). HHTg animals exhibited qualitative changes in NEFA fatty acid composition, represented by an increased proportion of saturated fatty acids (P < 0.05) and a decreased proportion of n-3 PUFA (P < 0.01). Ectopic lipid deposition in the kidneys of HHTg rats-triglycerides (+30%) and cholesterol (+10%)-was associated with markedly elevated microalbuminuria as ageing increased, despite the absence of microalbuminuria at the young age of 3 months in these animals. According to targeted proteomic analysis, 3-month-old HHTg rats (in comparison to age-matched controls) exhibited increased urinary secretion of proinflammatory parameters (MCP-1, IL-6, IL-8, P < 0.01) and decreased urinary secretion of epidermal growth factor (EGF, P < 0.01) before manifestation of microalbuminuria. Elevation in the urinary secretion of inflammatory cytokines can be affected by increased relative expression of MCP-1 in the renal cortex (P < 0.05). Conclusions: Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.

• MeSH
• Albuminuria etiology   urine   MeSH
• Urinalysis MeSH
• Biomarkers blood   urine   MeSH
• Early Diagnosis MeSH
• Time Factors MeSH
• Cytokines urine   MeSH
• Epidermal Growth Factor urine   MeSH
• Hypertriglyceridemia blood   complications   genetics   urine   MeSH
• Lipids blood   MeSH
• Inflammation Mediators urine   MeSH
• Metabolic Syndrome blood   complications   genetics   urine   MeSH
• Disease Models, Animal MeSH
• Kidney Diseases blood   etiology   urine   MeSH
• Rats, Transgenic MeSH
• Rats, Wistar MeSH
• Predictive Value of Tests MeSH
• Proteomics * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Cyclosporine toxicity   MeSH
• Hypertriglyceridemia blood   urine   MeSH
• Rats MeSH
• Kidney physiology   pathology   drug effects   MeSH
• Fatty Acids, Omega-3 pharmacology   MeSH
• Fish Oils MeSH
• Vitamin E pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Comparative Study MeSH