Abstract. Studied were the effects of myocardial infarction (MI) on mild renal function loss in unilateral nephrectomized (UnX) rats. UnX was performed, followed after 1 wk by a variable MI (UnX ϩ MI; n ϭ 24). Rats with only UnX (n ϭ 15) or MI (n ϭ 9) and double sham animals (CON, n ϭ 15) served as controls. Renal outcome was measured by proteinuria and plasma creatinine. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function and systolic BP were measured. A division into small and large infarcts after UnX was made a priori, resulting in two groups, one with a mild MI (Ͻ20%; n ϭ 15) and one with a moderate MI (Ͼ20%; n ϭ 9). Mild proteinuria up to 55.5 mg/d was observed in the UnX ϩ mild MI group, whereas proteinuria rose significantly higher to 124.5 mg/d in the UnX ϩ moderate MI group. Incidence of FGS was significantly increased in both UnX ϩ MI groups compared with all other groups. The average MI size was 18%, 17%, and 25% in the MI, UnX ϩ mild MI, and UnX ϩ moderate MI group, respectively. LVP in both UnX ϩ MI groups was correlated with proteinuria, indicative of a cardio-renal interaction. Clinically, these data imply that more patients are at risk for cardiovascular events and that after such an event, their chance of more renal function loss increases. Finding the underlying mechanism will enable improved protection for both kidneys and heart. Recent data from clinical studies have fueled the interest in the interaction between kidney and heart, and in particular the interaction between progressive function loss of both organs. The effect of renal impairment on cardiovascular function has been demonstrated in various studies. Patients with mild to severe renal insufficiency, including those patients starting renal replacement therapy, show an increased prevalence of cardiovascular disease (1-3), and Mann et al. (4) showed that impaired renal function increases the risk of cardiovascular events in the HOPE trial. Hillege et al. (5) found that impaired renal function is a stronger predictor of mortality than impaired cardiac function in advanced chronic heart failure. In addition, microalbuminuria is an independent risk factor for cardiovascular disease (6 -9). Although the mechanism behind the association between compromised renal function and the increased risk for cardiovascular disease remains unknown, it does not appear to involve common risk factors such as hypertension, diabetes, or hyperhomocystinemia (10). Although the effects of renal function impairment on cardiovascular mortality and morbidity have been extensively studied, it is unknown whether the opposite is also true-that is, whether cardiac function affects the outcome of mild renal function loss.The aim of the study presented here was to investigate whether cardiac damage could aggravate a mild state of chronic renal function loss. For this purpose, we used the rat model of unilateral nephrectomy (UnX) as this model shows a very mild state of chronic, mild renal function loss. In this model we introd...

MI does not further deteriorate structural renal damage induced by 5/6NX compared with 5/6NX alone. Furthermore, renal haemodynamic impairment occurs after MI, which can be improved applying ACEi therapy. Therefore, we conclude that treatment with ACEi should be optimized in patients with chronic kidney disease after MI to improve renal function.

Introduction High-sodium intake blunts the renoprotective efficacy of angiotensin-converting enzyme (ACE) inhibitors. We investigated whether targeting the drug to the kidneys may attenuate the inferior response to ACE inhibitor (ACE-I) under high-sodium conditions. The ACE-I, captopril, was coupled to the low molecular weight protein (LMWP) lysozyme, yielding captopril-lysozyme conjugates that accumulate specifically in the proximal tubular cells of the kidneys.We compared the antiproteinuric efficacy of captopril to that of the captopril-lysozyme conjugate in adriamycin-induced proteinuric rats fed with a high-sodium diet. Materials and methods Rats with adriamycin (single injection 2 mg/kg)-induced proteinuria were put on a high-sodium diet (HS; 3% NaCl). When stable proteinuria developed at 5.5 weeks, animals were assigned to the following subcutaneous treatments: (1) vehicle (n=7); (2) lysozyme (equivalent to the amount in conjugate) (n=7); (3) captopril (5 mg/kg/24 hours) (n=8); (4) captopril-lysozyme conjugate (captopril content equivalent to 1mg captopril/kg/24 hours) (n=7). Blood pressure and proteinuria were monitored. After 10 days of treatment the rats were sacrificed and kidneys and plasma were removed. Results Results are given as mean + S.E.M. After injection with adriamycin at t=0, stable proteinuria developed, amounting to 547+79 mg/24 hours at week 5.5. Subsequently, after seven and nine days of treatment, no reduction of proteinuria was observed in the captopril-treated group. In contrast, a significant reduction in proteinuria, amounting to 35+4% (day seven) and 25+2% (day nine), was observed in the captopril-lysozyme conjugate group (p<0.05 compared with the captopril group). In contrast, blood pressure was reduced in the captopril-treated group by 13.9+2.9 mmHg, while in the captopril-lysozyme treated group, an increase of 7.9+3.3 mmHg was found. Renal ACE activity was lowered by 30% in the captopril, as well as in the captopril-lysozyme conjugate treated group, compared with control. Furthermore, the ratio of kidney: plasma levels of captopril almost doubled as a consequence of coupling to lysozyme. Conclusion In proteinuric rats fed with a high-sodium diet, captopril induced a reduction in blood pressure without an effect on proteinuria. In contrast, renal targeting of a five times lower dose of the ACE-I with the captopril-lysozyme conjugate reduced proteinuria without reducing blood pressure. Therefore, renal targeting of ACE-I may be a promising strategy to optimise the therapeutic response of ACE-I.

Recently, it was shown that myocardial infarction aggravates preexistent mild renal damage that is elicited by unilateral nephrectomy in rats. The mechanism behind this cardiorenal interaction likely involves the renin-angiotensin-aldosteronesystem and/or vasoactive peptides that are metabolized by neutral endopeptidase (NEP). The renoprotective effect of angiotensin-converting enzyme inhibition (ACEi) as well as combined ACE/NEP inhibition with a vasopeptidase inhibitor (VPI) was investigated in the same model to clarify the underlying mechanism. At week 17 after sequential induction of unilateral nephrectomy and myocardial infarction, treatment with lisinopril (ACEi), AVE7688 (VPI), or vehicle was initiated for 6 wk. Proteinuria and systolic BP (SBP) were evaluated weekly. Renal damage was assessed primarily by proteinuria, interstitial ␣-smooth muscle actin (␣-SMA) staining, and the incidence of focal glomerulosclerosis (FGS). At start of treatment, proteinuria had increased progressively to 167 ؎ 20 mg/d in the entire cohort (n ‫؍‬ 42). Both ACEi and VPI provided a similar reduction in proteinuria, ␣-SMA, and FGS compared with vehicle at week 23 (proteinuria 76 ؎ 6 versus 77 ؎ 4%; ␣-SMA 60 ؎ 6 versus 77 ؎ 3%; FGS 52 ؎ 14 versus 61 ؎ 10%). Similar reductions in systolic BP were observed in both ACEi-and VPI-treated groups (33 ؎ 3 and 37 ؎ 2%, respectively). Compared with ACEi, VPI-treated rats displayed a significantly larger reduction of plasma (41 ؎ 5 versus 61 ؎ 4%) and renal (53 ؎ 6 versus 74 ؎ 4%) ACE activity. It is concluded that both ACEi and VPI intervention prevent renal damage in a rat model of cardiorenal interaction. VPI treatment seemed to provide no additional renoprotection compared with sole ACEi after 6 wk of treatment in this model, despite a more pronounced ACE-inhibiting effect of VPI.