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Exercise training (Ex) slows the progression of hypertension and renal failure in some animal models. We and other groups have reported that Ex ameliorated hypertension and renal dysfunction in spontaneously hypertensive rats. Since little has been reported on the effects of Ex on renal disorder in salt-sensitive hypertension, we investigated the effects of Ex on blood pressure and renal function in Dahl salt-sensitive (DS) rats. Six-week-old male DS rats were divided into three groups: 1) Normal salt (0.5% NaCl) diet (NS) (NS group, n=10), 2) High salt (8% NaCl) diet (HS) (HS group, n=11), 3) HS plus moderate Ex with treadmill running (HE group, n=11). After 8 weeks, HS induced severe hypertension, and Ex did not affect systolic blood pressure (114±3, 209±6 and 205±8 mmHg in the NS, HS and HE groups, respectively). Plasma creatinine was significantly higher in the HS and HE groups than in the NS group, but not different between the HS and HE groups (0.22±0.01, 0.44±0.03 and 0.40±0.03 mg/dl). Urinary protein and albumin significantly increased in the HS and HE groups, but these were significantly lower in the HE group compared with the HS group (Protein: 15.9±1.6, 432.8±36.8 and 327.2±22.3 mg/day. Albumin: 3.9±0.8, 195.2±15.2 and 154.2±11.1mg/day). Urinary TBARS, an index of oxidative stress, significantly increased in the HS and HE groups, but this was significantly lower in the HE group compared with the HS group (0.30±0.02, 0.75±0.06 and 0.53±0.03 mg/day); there was no significant difference in plasma TBARS among all groups. CYP4A1 and CYP4A2 protein expressions in the outer medulla were significantly lowered by 37% and 48% in the HS group compared with the NS group, and were significantly elevated by 40% and 150% in the HE group compared with the HS group. There was no significant difference in cortical CYP4A1 protein expression among all groups. Although there was no difference in cortical CYP4A2 between the NS and HS groups, it was significantly increased by 35% in the HE group compared with the HS group. These results suggest that Ex attenuated HS-induced proteinuria independently of blood pressure or plasma creatinine level in DS rats. The improvement of oxidative stress and CYP4A expression in the kidneys may contribute to the renoprotective effects of Ex in DS rats. [ABSTRACT FROM AUTHOR]

Alubuminuria is an aggravating factor for chronic kidney disease. Fatty acids bound to albumin are overloaded to the proximal tubules in alubuminuria and contribute to tubulointerstitial damage. It is known not only the β-oxidation ability but the ability of cytochrome P450 (CYP) metabolism of arachidonic acid (AA) is high in the kidney. Epoxyeicosatrienoic acids synthesized primarily by CYP2C and 20-hydroxyeicosatetraenoic acid synthesized by CYP4A affect tubular function and renal circulation. However, it isn’t clear CYP metabolism of AA would change in alubuminuria. The study tested changes of CYP metabolism of AA in the kidney of nephrotic rats. Sprague-Dawley rat (SD) and Nagase Analbuminemic rat (NAR) with inherited hypoalbuminemia were used and nephrotic syndrome was induced by Puromycin Aminonucleoside (PAN; 100 mg/kg, iv). Rats were randomly divided into four groups; (1) SD group; (2) SD treated with PAN group (PAN group); (3) NAR group; (4)NAR treated with PAN group (NAR+PAN group). Rats were killed on the 14th day and urinary 8OHdG, a marker of oxidative stress in the kidney, and urinary NAG, a marker of proximal tubular cell damage, were measured. The protein level of enzymes in the kidney was analyzed by Western blot and immunohistochemistry. Compared with the SD group, albuminuria, 8OHdG and NAG increased respectively to 847%, 154% and 903% in the PAN group, and Western blot showed the protein levels of CYP2C23 and CYP4A decreased to 45% and 49% without change of the protein level of PPARα, a nuclear receptor regulating fatty acid metabolism, in the PAN group. Immunohistochemistry showed the localization of CYP2C23 and CYP4A in the proximal tubule and confirmed the results by Western blot. Otherwise, we could find no difference in albuminuria, tubulointerstitial damage and the protein level of CYP2C23 between the NAR group and the NAR+PAN group. Compared with the NAR group, the protein level of CYP4A decreased to 68% in the NAR+PAN group. Alubuminuria caused tubulointerstitial damage and decreased the expressions of CYP2C23 and CYP4A in the nephrotic kidney. This study suggested the disorder of CYP metabolism of AA would affect renal circulation in alubuminuria and CYP4A would be affected by anything except alubuminuria in PAN rats. [ABSTRACT FROM AUTHOR]

It has been recently reported that the exercise training (Ex) increases nitric oxide (NO) production and NO synthase (NOS) expression not only in vasculatures but also in the kidney of spontaneously hypertensive rats (SHR) with the reduction of systemic blood pressure. To clarify the mechanism of the Ex-increased NOS expression, the impacts of inhibitors of NADPH oxidase and xanthine oxidase on the Ex-increased NOS activity and expression were examined in SHRs and Wistar-Kyoto rats (WKY). Five week-old, male SHR or WKY were trained with treadmill running. Apocynin (2 mmol/L in drinking water), an inhibitor of NADPH oxidase or allopurinol (1.5 mmol/L in drinking water), an inhibitor of xanthine oxidase was given for drug treatments. After 8 weeks, H2O2 and NO2/NO3 (NOx) in plasma and urine were measured. The NOS activity and expression were examined in the kidney cortex, the outer medulla, the inner medulla and thoracic aorta. In both SHR and WKY, the Ex significantly increased H2O2 and NOx in plasma and urine, NOS activity and endothelial and neuronal NOS (eNOS and nNOS) expressions in the kidney cortex, the outer medulla, the inner medulla and thoracic aorta (p<0.01 in each). Apocynin significantly decreased basal levels of H2O2 and NOx in plasma and urine, NOS activity and eNOS and nNOS expressions (p<0.01 in each) in the kidney sections and aorta of SHR, but did not affect all parameters in those of WKY. Apocynin blocked the Ex-induced changes of H2O2 and NOx levels and renal and aortic NOS activity and expression in WKY and aortic NOS activity and expression in SHR, but it did not block the Ex-induced changes of H2O2 and NOx levels or renal NOS activity and expression in SHR. In contrast to apocynin, allopurinol did not affect basal levels of all these parameters in SHR or WKY. Allopurinol blocked the Ex-induced changes of H2O2 and NOx levels and renal NOS expression in SHR but did not block the Ex- induced changes of aortic NOS expression in SHR or all parameters in WKY. These results indicate that the Ex-increased NOS activity and expression in aorta were mediated through NADPH oxidase in both SHR and WKY. The Ex-induced NOS activity and expression in the kidney were mediated through NADPH oxidase in WKY but through xanthine oxidase in SHR. [ABSTRACT FROM AUTHOR]