Abstract
Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been proposed as supplementary approach in patients with initial diabetic nephropathy. However, the molecular mechanism(s) underlying its protective role has been so far slightly examined. C57Bl/6J mice were fed with a standard diet (SD) or a diet enriched in fat and fructose (HD) for 12 weeks. After 3 weeks, two subgroups of SD and HD mice started pyridoxamine supplementation (150 mg/kg/day) in the drinking water. HD fed mice showed increased body weight and impaired glucose tolerance, whereas pyridoxamine administration significantly improved insulin sensitivity, but not body weight, and reduced diet-induced increase in serum creatinine and urine albumin. Kidney morphology of HD fed mice showed strong vacuolar degeneration and loss of tubule brush border, associated with a drastic increase in both advanced glycation end products (AGEs) and AGEs receptor (RAGE). These effects were significantly counteracted by pyridoxamine, with consequent reduction of the diet-induced overactivation of NF-kB and Rho/ROCK pathways. Overall, the present study demonstrates for the first time that the administration of the antiglycative compound pyridoxamine can reduce the early stages of diet-dependent kidney injury and dysfunction by interfering at many levels with the profibrotic signaling and inflammatory cascades.
Highlights
One of the most feared chronic microvascular complications of diabetes is diabetic nephropathy
Mice fed with the high-fat highfructose diet (HD) for 12 weeks had greater body weights than control diet-fed littermates (SD) (Table 1)
The concentration of fasting serum glucose, but not insulin, was significantly reduced by daily administration of pyridoxamine (HD + P), remaining still higher than that recorded in the standard diet (SD) group
Summary
One of the most feared chronic microvascular complications of diabetes is diabetic nephropathy. Diabetes is the leading cause of end-stage renal disease, surpassing other etiologies, such as hypertension. An early sign of diabetic nephropathy is an increased protein release in urine, displayed as microalbuminuria, which is associated with the progression of renal damage, and is caused by glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubule-interstitial fibrosis, glomerulosclerosis, and podocytopathy [3]. Established therapeutic approaches for diabetic nephropathy are primarily antihypertensives that act on renin angiotensin aldosterone system, such as angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers. These appear to reduce proteinuria and to delay, but not prevent, the onset of end-stage renal disease [4]
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