The Effect of Lipotoxicity on Renal Dysfunction in a Nonobese Rat Model of Metabolic Syndrome: A Urinary Proteomic Approach

Abstract

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.

Crescent-Like Lesions as an Early Signature of Nephropathy in a Rat Model of Prediabetes Induced by a Hypercaloric Diet

“…These possibilities are in line with the association between obesity/adiposity and increased risk of GFR decline and mortality in individuals with and without CKD [27]. Renal damage induced by lipotoxicity is a complex process that has been progressively disclosed [60,61]. The increased renal expression of IL-6, regardless of normal serum hs-CRP, might be linked to hyperglycemic and hyperlipidemic stimuli, as previously suggested [62,63].…”

“…In our model, hyperglycemia or hyperlipidemia induced by HSuHF diet might be the driven forces for the metabolic damage (via glucotoxicity and lipotoxicity) underlying the formation of psudocrescents. Despite the absence of a clear inflammatory phenotype, at both systemic and renal levels, the existence of oxidative stress and renal lipidosis might explain the renal damage, as previously suggested by others [59,60]. These possibilities are in line with the association between obesity/adiposity and increased risk of GFR decline and mortality in individuals with and without CKD [27].…”

Metformin Affects Cardiac Arachidonic Acid Metabolism and Cardiac Lipid Metabolite Storage in a Prediabetic Rat Model

“…With the exception of myocardial TG, cardiac energy metabolism depends on the availability, concentration and composition of circulating NEFA. As previously described [ 20 ], the hypertriglyceridemic rat strain exhibits chronically elevated circulating NEFA levels, accompanied by qualitative alterations in NEFA lipid classes, manifesting in both increased SFA and decreased n3-PUFA profiles. Aggravated NEFA metabolism and genetically determined hypertriglyceridemia in HHTg rats combine to promote ectopic lipid deposition in different tissues, including the liver, muscle and heart.…”

The Vasoactive Role of Perivascular Adipose Tissue and the Sulfide Signaling Pathway in a Nonobese Model of Metabolic Syndrome

“…Cardiac hypotrophy could be related to the fact that hypertriglyceridemia and metabolic syndrome are associated with increased lipid accumulation in nonadipose tissues. Ectopically stored lipids and their metabolites (diacylglycerols, ceramides, and fatty acyl-CoAs) in the liver, heart, muscles, and kidney lead to lipotoxicity, which may result in tissue injury [ 17 , 18 ]. We found increased levels of kidney and liver injury markers, such as alanine-aminotransferase, which also demonstrates myocardial damage [ 19 ].…”