Glucose degradation products result in cardiovascular toxicity in a rat model of renal failure.

BACKGROUND: It has been shown that glucose degradation products (GDP) generated during heat sterilization of peritoneal dialysis (PD) fluids impair the peritoneal membrane locally, then enter the systemic circulation and cause damage to the remnant kidney. Here we examined in subtotally nephrectomized (SNX) rats whether GDP also affect the cardiovascular system. MATERIALS AND METHODS: Standard 5/6 nephrectomy was carried out in Sprague-Dawley rats; other rats were sham operated and left untreated for 3 weeks. Through an osmotic mini-pump, SNX+GDP group received GDP intravenously for 4 weeks; the SNX and the sham-operated groups remained without GDP. The experiment was terminated for all groups 7 weeks postoperatively. We analyzed cardiovascular damage by serum analyses and immunohistochemical investigation. RESULTS: In SNX+GDP animals, expression of the advanced glycation end product (AGE) marker carboxymethyllysine and receptor of AGE (RAGE) were significantly higher in the myocardium and the aorta compared to the SNX rats. We also found significantly higher levels of apoptosis measured by caspase 3 staining in the cardiovascular system in the SNX+GDP group. Moreover, we observed a more pronounced expression of oxidative stress in the SNX+GDP rats compared to the SNX rats. In serum analyses, advanced oxidation protein products and reactive oxygen species were increased, as was immunohistochemical endothelial nitric oxide synthase. CONCLUSIONS: In addition to local toxic effects, GDP cause systemic toxicity. Here we showed that, in SNX rats, administration of GDP increased cardiovascular damage. In particular, we found increased levels of AGE, RAGE, oxidative stress, and apoptosis. Whether these findings are of clinical relevance has to be further investigated.

Chronic low-dose isotretinoin treatment limits renal damage in subtotally nephrectomized rats.

Retinoids are anti-proliferative and anti-inflammatory compounds. We had previously shown that retinoids alleviate kidney damage in acute models of renal disease. We now examined whether retinoids are also effective in a chronic renal ablation model. Subtotally nephrectomized rats (SNx; two-third ablation) were compared to sham-operated controls (sham). SNx rats were administered either 10 mg/kg b.w. (low dose, LD) or 40 mg/kg b.w. (high dose, HD) isotretinoin or vehicle (n = 10 per group). The experiment was terminated after 16 weeks. Systolic blood pressure was significantly higher after SNx compared to sham but lower in SNx with LD isotretinoin (vs. SNx + vehicle). Compared to SNx + vehicle, SNx + LD isotretinoin had lower glomerular cell numbers, less glomerular hypertrophy and sclerosis, and less interstitial expansion. Morphological improvement in SNx + LD isotretinoin was accompanied by improvement in creatinine clearance and reduced urinary albumin excretion. In contrast, HD isotretinoin caused aggravation of renal damage with fibrinoid necroses of vessels and elevated urinary albumin excretion despite lower blood pressure. The dichotomous effects of isotretinoin are at least in part due to time- and dose-dependent alterations of transforming growth factor beta1 and collagen IV gene expression as also suggested by cell-culture studies in vascular smooth muscle cells. In addition, isotretinoin affected the systemic and the renal renin-angiotensin system (which was further analyzed in a model of angiotensin II infusion of the rat). Isotretinoin failed to cumulate at LD but cumulated at HD in SNx. We conclude that LD isotretinoin attenuates progressive renal damage, whereas HD isotretinoin cumulates and aggravates renal damage independent of blood pressure reduction.