Elevated serum uric acid concentration is a common laboratory finding in subjects with metabolic syndrome/obesity, hypertension, kidney disease and cardiovascular events. Hyperuricemia has been attributed to hyperinsulinemia in metabolic syndrome and to decreased uric acid excretion in kidney dysfunction and is not acknowledged as a main mediator of metabolic syndrome, renal disease, and cardiovascular disorder development. However, more recent investigations have altered this traditional view and shown by providing compelling evidence to support an independent link between hyperuricemia and increased risk of metabolic syndrome, diabetes, hypertension, kidney disease and cardiovascular disorders. However, despite these new findings, controversy regarding the exact role of uric acid in inducing these diseases remains to be unfolded. Furthermore, recent data suggest that the high-fructose diet in the United State, as a major cause of hyperuricemia, may be contributing to the metabolic syndrome/obesity epidemic, diabetes, hypertension, kidney disease and cardiovascular disorder. Our focus in this review is to discuss the available evidence supporting a role for uric acid in the development of metabolic syndrome, hypertension, renal disease, and cardiovascular disorder; and the potential pathophysiology mechanisms involved.

The prevalence of obesity in the United States remains high, exceeding 30% in most states. As this trend continues unhindered, we will continue see a persistent rise in obesity-related metabolic effects—hypertension, dyslipidemia, diabetes mellitus, and atherosclerosis. These diseases are also the leading causes of chronic kidney diseases and end-stage renal disease. The lipid nephrotoxicity hypothesis, proposed over three decades ago, suggested that proteinuria, decreased albumin levels, and the resultant hyperlipidemia may cause a glomerulosclerosis similar to atherosclerosis. More recent studies have demonstrated the role of oxidized high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles in the progression of kidney disease. Elucidation of the role of lipid-lowering therapies and the concomitant improvement in tubulointerstitial and glomerular diseases is a further evidence of the role of lipids in renal injury. Synergistic effects of lipid-lowering drugs and blockers of the renin-angiotensin-aldosterone system (RAAS) in renal protection have also been documented. Dyslipidemia in renal disease is usually characterized by elevated LDL cholesterol, low HDL cholesterol, and high triglycerides. After an initial glomerular injury, likely to be inflammatory, a series of self-perpetuating events occur. Increased glomerular basement permeability leads to loss of lipoprotein lipase activators, which results in hyperlipidemia. Circulating LDL has a charge affinity for glycoaminoglycans in the glomerular basement membrane and further increases its permeability. Substantial amounts of filtered lipoprotein cause proliferation of mesangial cells. Proximal tubules reabsorb some of the filtered lipoprotein, and the remainder is altered during passage through the nephron. If intraluminal pH is close to the isoelectric point of the apoprotein, luminal apoprotein will precipitate, causing tubulointerstitial disease. This review shows the evidence for the role of lipids in development of chronic renal disease, the pathophysiology of lipid nephrotoxicity, and strategies available to clinicians to slow the progression of disease.

Apolipoprotein Cs (apoC-1, apoC-II, and apoC-III) are lipoprotein components that have regulatory effects on enzymes involved in lipoprotein metabolism. Owing to their low molecular weights, apoCs can adsorb onto and/or pass through dialysis membranes. Our study determines the consequence of hemodialysis (HD) on plasma concentrations of apoCs and on the activities of enzymes modulated by apoCs. Plasma samples were collected from 28 patients with chronic renal failure before and after HD. Plasma apoC-II levels were unchanged, whereas apoC-III levels were slightly decreased in post-dialysis plasmas. The apoC-I content was markedly reduced during HD. This was due to a significant decrease in the apoC-I content of very low-density lipoprotein (VLDL), whereas the apoC-I content of high-density lipoprotein (HDL) was unchanged. Although HDL bound apoC-I is thought to inhibit cholesterol ester transfer protein, no change in the ability of pre- and post-dialysis VLDL to interact with the transfer protein were observed. Complementary experiments confirmed that VLDL-bound apoC-I has no transfer protein inhibitory potential. In contrast, an increase in the ability of post-dialysis apoC-I-poor VLDL to act as substrate for lipoprotein lipase (LPL) was found compared to pre-dialysis VLDL. Our study shows that apoC-I losses during HD might be beneficial by improving the ability of VLDL to be a substrate for LPL thus improving plasma triglyceride metabolism.

There is a neglected epidemic of both obesity and metabolic syndrome in industrialized and unindustrialized countries all over the globe. Both conditions are associated with a high incidence of other serious pathologies, such as cardiovascular and renal diseases. In this article, we review the potential underlying mechanisms by which obesity and metabolic syndrome promote hypertension, including changes in cardiovascular-renal physiology induced by leptin, the sympathetic nervous system, the renin-angiotensin-aldosterone system, insulin resistance, free fatty acids, natriuretic peptides, and proinflammatory cytokines. We also discuss the potential underlying mechanisms by which obesity promotes other cardiovascular and renal conditions, as well as available nonpharmacologic and pharmacologic approaches for treating obesity-induced hypertension. The findings presented herein suggest that adipocytes may be a key regulator of cardiovascular and renal function.

Aims: We investigated the effects of the nuclear factor kappa B (NFκB) blocker pyrrolidine dithiocarbamate (PDTC) on high-fat diet (HFD)-induced metabolic and renal alterations in obese and lean Zucker rats (OZR and LZR, respectively).Main methods: Rats were fed a HFD resembling the typical "Western" diet or a regular diet (RD) and allowed free access to tap water or tap water containing PDTC (150 mg/kg body weight) for 10 weeks; rats were then sacrificed. Total ROS production rates were measured using electron paramagnetic resonance spectroscopy, and superoxide production was measured with lucigenin assay. Blood, plasma, and urine were analyzed. Semi-quantitative reverse transcriptase-polymerase chain reaction and electrophoretic mobility shift assay were conducted to assess NFκB mRNA levels and DNA binding activities, respectively; immunofluorescence was performed to assess protein levels.Key findings: OZR-HFD rats exhibited significantly higher levels of total renal cortical reactive oxygen species production, plasma lipids, insulin, C-reactive protein, blood urea nitrogen, creatinine, and urinary albumin excretion than all other groups (p<0.05); these changes were accompanied by a significant decrease in plasma high density lipoprotein levels (p<0.05). Gene expression levels of desmin, cytokine and oxidative stress genes were significantly higher in the renal cortical tissues of OZR-HFD; NFκB p65 DNA binding activity was also significantly higher in these animals. PDTC attenuated these changes.Significance: Our data suggest that NFκB blockade may prove beneficial in treating the nephropathy often associated with metabolic syndrome.