Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure.

Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n=10) or subtotal nephrectomy (SNX, n=10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258±2,078 units) than in both sham groups (11,709±4,169 and 8,998±4,823 units); this decrease was significantly prevented by renal denervation (8,190±3,889, P<0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression.

[Neoangiogenesis: from molecular biology to clinical medicine]. / La neoangiogenesi: dalla biologia molecolare alla clinica.

Cardiovascular disease is the most common cause of premature death in patients with end-stage renal disease, probably due to a specific "uraemic cardiomyopathy" This article reviews the pathogenesis of cardiac changes in uraemia and particularly the role of an impaired vessel formation. Experimental and autoptic data showed remarkable changes in heart capillarization in renal failure, i.e. a decrease in myocardial capillary supply and a concomitant increase in intercapillary distance. Promoting the formation of new collateral vessels in ischemic tissues using angiogenic growth factors (therapeutic angiogenesis), such as VEGF, constitutes a promising approach for the treatment of uraemic cardiomyopathy.

Lacidipine reduces high blood pressure and the target organ damage induced by high fructose diet in rats.

OBJECTIVE: Normotensive rats fed a high fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine could be effective not only in preventing, but also in inducing the regression of hypertension, and renal and cardiac damage in rats fed HFD. METHODS: Thirty male Wistar-Kyoto (WKY) rats received HFD for 1 month; thereafter, five rats were sacrificed (Group 1) and the other 25 rats were divided into three groups: Group 2 (five rats) received HFD plus placebo, Group 3 (10 rats) HFD plus lacidipine 3 mg/kg per day, and Group 4 (10 rats) HFD plus hydralazine 10 mg/kg per day. At the end of the second month all animals were sacrificed. Kidneys and hearts were immediately removed. Renal deposits of collagen I, collagen IV, fibronectin and cardiac deposits of collagen III were assessed by means of immunohistochemistry. RESULTS: In the rats receiving HFD plus placebo, blood pressure was increased after the first and the second month of diet. This increase was reversed by lacidipine and hydralazine but, although both drugs normalized blood pressure, only lacidipine was effective in reducing renal and cardiac damage. CONCLUSIONS: These data suggest that lacidipine is effective in reversing hypertension and reducing target organ damage induced by HFD. Moreover, this protective effect on target organs appears to be not simply a consequence of blood pressure reduction, but seems to be connected to the type of hypotensive drug administered.

The ET(A) receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model.

The effect of the orally highly bioavailable and specific endothelin A (ET(A)) receptor antagonist LU 135252 was assessed in a model of chronic renal allograft nephropathy. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Fisher autografts and kidneys after uninephrectomy served as controls. All animals received low-dose cyclosporin A (CsA; 1.5 mg/kg body wt) for 10 d after surgery. Allotransplanted animals were then randomized to receive standard diet or a diet designed to deliver 30 mg of LU 135252/kg body wt per d for 35 wk. BP was monitored telemetrically. Treatment with LU 135252 did not affect systolic or diastolic pressure. Indices of glomerulosclerosis (GSI), and tubulointerstitial and vascular damage were measured. Chronic transplant nephropathy was almost completely prevented by LU 135252 compared with untreated allografts or kidneys of uninephrectomized controls, i.e., GSI 0.7 +/- 0.12 versus 1.6 +/- 0.25 (P < 0.001) versus 0.7 +/- 0.06 (P < 0.001). Allograft weight and serum creatinine were significantly lower in treated versus untreated animals. The results are consistent with the notion that ET(A) receptor-mediated events play a role in the genesis of chronic transplant nephropathy.

Lacidipine prevents the hypertension and renal and cardiac changes induced by high-fructose diet in WKY rats.

Normotensive rats fed a high-fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia, and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine, a calcium antagonist, could have a protective effect with this animal model. Forty male Wistar-Kyoto (WKY) rats were divided into four groups treated with HFD + placebo; HFD + lacidipine, 0.3 mg/kg/day; HFD + lacidipine, 3 mg/kg/day; or standard diet + placebo for 4 weeks. Urinary excretion of the stable metabolic products of nitric oxide (NO) was determined, because this vasoactive agent has been found to cause hemodynamic changes in the diabetic kidney. Glomerular size was determined by means of morphometric analysis. The results of this study show that lacidipine prevents (a) the HFD-induced increase in blood pressure in a dose-dependent manner; (b) the HFD-induced increase in glomerular size and fibronectin synthesis; and (c) the increase of collagen III synthesis in the heart. The drug had no effect on the increased urinary excretion of the stable metabolic products of NO. These data suggest that lacidipine might be useful in preventing the renal and cardiac damage caused by hypertension and non-insulin-dependent diabetes mellitus.

Diabetic nephropathy--what have we learned in the last three decades?

The past three decades have seen enormous conceptual advances in understanding the pathogenesis of diabetic nephropathy. Increasing evidence points to important genetic determination of the renal risk, i.e. the propensity to develop diabetic nephropathy, in type 1 and type 2 diabetic patients. We are also further along the path to understanding the abnormalities of renal hemodynamics that underly these patients' propensity to develop diabetic glomerulosclerosis, i.e. afferent arterial vasodilation and increased glomerular pressure, identified in elegant experimental studies. Another important advance is the recognition that increased urinary albumin excretion is not only an extremely sensitive marker, but also an important player in the pathogenesis of diabetic nephropathy. Finally, the concept of the toxicity of hyperglycemia ("glucotoxicity") has been carried to the molecular level, so that pathomechanisms such as activation of protein kinase C and cellular damage by advanced glycation endproducts (AGE), to name only two, have been elucidated. Diabetic nephropathy has become the leading cause of endstage renal failure (ESRF) in Western countries, particularly in patients with type 2 diabetes. Three treatment modalities are available: (i) hemodialysis,(ii) CAPD and (iii) transplantation, meaning kidney transplantation, combined pancreas and kidney transplantation or - still in a very preliminary stage - islet cell transplantation. The ideal is to have all three modalities available to meet each patient's individual needs. Treatment outcome continues to be considerably worse, however, in diabetic than non-diabetic patients. This highlights the importance of prevention. Progression to ESRF in diabetic nephropathy is preventable, at least to a large extent.