Abstract
Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD) on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-α and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment.
Highlights
Diabetic nephropathy (DN) is one of the most important microvascular complications and the major determinant of morbidity and mortality in diabetic patients
Chronic hyperglycemia is a major cause of DN, other factors such as obesity, dyslipidemia and hypertension have been implicated in the development of DN, where genetic and environmental factors are responsible for triggering a complex series of pathophysiological events [1, 2], and initiation sometimes occurs before overt hyperglycemia is seen
Western diet (WD), another representative atherogenic diet, increased urinary albumin excretion (UAE) of Otsuka Long Evans Tokushima Fatty (OLETF) rats, but the increment was much smaller than that seen in OLETF rats fed Paigen diet (PD) (Fig 1A), and glomerular mesangial areas were little changed by WD (Fig 1B)
Summary
Diabetic nephropathy (DN) is one of the most important microvascular complications and the major determinant of morbidity and mortality in diabetic patients. Chronic hyperglycemia is a major cause of DN, other factors such as obesity, dyslipidemia and hypertension have been implicated in the development of DN, where genetic and environmental factors are responsible for triggering a complex series of pathophysiological events [1, 2], and initiation sometimes occurs before overt hyperglycemia is seen. The specific roles of these authors are articulated in the "Author contributions" section of the online submission form
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