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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. [ABSTRACT FROM AUTHOR]

In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated + vehicle-treated rats (controls); (2) SNX + vehicle-treated rats (SNX); (3) parathyroidectomized SNX + vehicle-treated rats (SNX+PTX); and (4) SNX + calcimimetic R-568-treated rats (SNX+R-568). R-568 (50 micro mol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568-treated and parathyroidectomized SNX compared with vehicle-treated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicle-treated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.

Background: The effect of the specific endothelin (A) (ET(A))-receptor antagonist LU 302146 (LU) was assessed in a normotensive model of chronic transplant vasculopathy, i.e. orthotopic allotransplantation of the infrarenal abdominal aorta from spontaneously hypertensive-to-Wistar-Kyoto (SHR-to-WKY) rats. A second experimental setting was used to confirm the results in a different model, which to some extent may also address the issue of blood pressure (BP) in transplant vasculopathy, i.e. orthotopic allotransplantation of infrarenal abdominal aorta from WKY-to-SHR rats. Untreated sham-operated and isografted WKY and SHR served as controls. Allotransplanted animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril served as positive treatment controls., Methods: Rats were randomized to receive standard diet or a diet designed to deliver either 30 mg LU/kg bw/day, 0.3 mg/kg bw/day trandolapril or a combination of both. The duration of either experiment was 8 weeks. BP was measured by tail plethysmography., Results: Treatment with LU did not affect systolic BP in either experimental setting. In contrast, trandolapril and combination treatment significantly reduced systolic BP in SHRs. The increase in aortic wall thickness (given in mm) was abrogated to a similar extent in the three treatment groups as compared with untreated allotransplanted animals in either experimental setting (e.g. WKY sham-operated 0.084 +/- 0.013, P < 0.05 vs treatment groups; WKY isotransplanted 0.100 +/- 0.010, P < 0.05 vs treatment groups; WKY allotransplanted 0.289 +/- 0.077, P < 0.05 vs all groups; WKY allotransplanted + trandolapril 0.185 +/- 0.025; WKY allotransplanted + LU 301246 0.192 +/- 0.049; WKY allotransplanted + LU 301246 + trandolapril 0.190 +/- 0.041). This was due to an attenuation of the increase of intima and media thickness. Treatment with LU and trandolapril were similarly effective in attenuating the increase of the number of proliferating cell nuclear antigen (PCNA)-positive cells in the intima. Again, combination treatment did not confer additional benefit. In contrast, trandolapril was more effective than LU in attenuating the increase in the number of PCNA-positive cells in the media. Trandolapril or combination treatment, but not LU, attenuated transforming growth factor-beta expression in aortic allografts., Conclusions: The ET(A)-receptor blockade abrogates allograft vasculopathy in two different aorta allotransplantation models to a similar extent as ACE inhibition even in the absence of concomitant immunosuppression. At least in SHRs the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of chronic transplant vasculopathy.

Background: Cigarette smoking increases the risk of progression of diabetic and non-diabetic renal diseases. The mechanisms underlying the adverse effects of smoking are largely unknown. We examined the subtotally nephrectomized rat (i) to investigate whether components of cigarette smoke dissolved in acetone (cigarette smoke condensate) aggravate structural renal damage and (ii) to establish whether this provides an animal model that can be used to investigate potential pathomechanisms of cigarette smoke-induced renal damage. Since nicotine activates the sympathetic nerve system in humans, we investigated whether interference with this system modulates the effects of cigarette smoke condensate on the damaged kidney., Methods: One group of Sprague-Dawley rats was subtotally nephrectomized (SNX). Acetone (SNX + solvent) or cigarette smoke condensate (SNX + cigarette) was applied daily to the oral mucosa. Another group of Sprague-Dawley rats was sham-operated and received the same treatments (sham + solvent, sham + cigarette). To investigate whether increased activity of the sympathetic nerve system is involved, the remnant kidney was denervated by microsurgical technique in one SNX + cigarette group. The control group for this intervention was a solvent-treated SNX group with denervated remnant kidney. Blood pressure (BP) was measured weekly by tail plethysmography. The experiment was terminated after 12 weeks. Structural renal damage was assessed by morphometric techniques (indices of glomerulosclerosis, tubulointerstitial and vascular damage) and urinary albumin and endothelin-1 excretion were measured., Results: Indices of structural renal damage were increased in all SNX-groups. Treatment with cigarette smoke condensate further increased the indices of glomerulosclerosis and tubulointerstitial damage in SNX, but not sham-operated rats. This increase was completely prevented by renal denervation. No differences in systemic blood pressure were observed in the different SNX groups. Urinary albumin excretion went in parallel with the indices of glomerulosclerosis and tubulointerstitial damage and urinary endothelin-1 excretion was significantly increased in SNX + cigarette animals., Conclusion: These findings document that acetone soluble components in cigarette smoke aggravate glomerulosclerosis and tubulointerstitial damage in the renal ablation model. Renal injury induced by cigarette smoke condensate in this model is reversed by renal denervation. We conclude that cigarette smoke-induced renal damage is due, at least in part, to activation of the sympathetic nerve system.

Background: Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection., Methods: We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment., Results: LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies., Conclusions: We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.

Background: Early glomerular hypertrophy and late glomerulosclerosis have been observed in rats fed high fructose diet (HFD), comparable with those of diabetic rats. Several studies suggest a role for nitric oxide (NO) in the pathogenesis of renal damage in diabetes. This study investigated the possible role of NO in the pathogenesis of HFD-induced glomerular changes., Methods: Three study protocols were adopted. In the first, 20 rats were divided into two groups to evaluate the effect of HFD on glomerular size and on the urinary excretion of NO. In the second, the glomerular size was evaluated in 40 rats divided into four groups receiving: (1) standard diet (SD); (2) HFD; (3) HFD + L-NAME, and (4) SD + L-NAME for 1 month. In the third, the renal expression of inducible enzyme (iNOS) was compared in 10 rats on HFD and in 10 controls after a 1-month diet., Results: The results showed: (1) increased urinary excretion of NO and glomerular size, both induced by HFD; (2) prevention by L-NAME of the HFD-increased glomerular size, and (3) increased iNOS expression in the kidneys of rats fed HFD., Conclusion: These results suggest a role for NO in the pathogenesis of the early renal changes induced by HFD., (Copyright 2002 S. Karger AG, Basel)

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.

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.

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.

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.