Sakae Ohkawa

Association between inflammatory mediators and muscle mass in long-term hemodialysis patients

BACKGROUND Muscle wasting is highly prevalent in long-term hemodialysis (HD) patients. Although inflammatory indices have been associated with malnutrition in these patients, the role of inflammation in muscle wasting has not yet been determined. METHODS The relationship between the inflammatory mediators C-reactive protein (CRP) and interleukin-6 (IL-6) and the muscle mass indices thigh muscle area (TMA), measured by computed tomography, and creatinine (Cr) production, estimated by the Cr kinetic model (Cr-CKM), were investigated in 188 HD patients. RESULTS Serum IL-6 level (7.3 +/- 7.8 pg/mL) was significantly elevated in HD patients, whereas mean serum CRP level (4.8 +/- 7.5 mg/L) remained within the normal range. Similar to serum albumin, muscle mass indices had significantly negative correlations with both serum IL-6 and CRP levels (TMA/dry weight [DW] versus log IL-6, r = -0.28; P < 0.01; TMA/DW versus log CRP, r = -0.38; P < 0.001; Cr-CKM versus log IL-6, r = -0.31; P < 0.01; Cr-CKM versus log CRP, r = -0.24; P < 0.01). Although muscle mass indices also were associated with both age and sex, a multiple regression analysis confirmed that these inflammatory indices were significantly associated with muscle mass in HD patients. CONCLUSION Data indicate that muscle wasting is associated closely with inflammatory indices in long-term HD patients. It may be important to clarify the mechanism for the increasing inflammatory status and suppress the inflammatory response in these patients to improve their malnutrition and recover muscle mass.

Relaxin ameliorates salt-sensitive hypertension and renal fibrosis

BACKGROUND Although relaxin (RLX) has potent vasodilatory and anti-fibrotic properties, there is no information on its effects on salt-sensitive hypertension. METHODS We investigated the effects of short-term treatment with RLX on blood pressure (BP) and nitric oxide synthase (NOS) protein in the kidneys of male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats after 1 week consumption of an 8% NaCl diet. We also evaluated the inhibitory effects of each specific NOS inhibitor on BP during 1-week RLX treatment under high-salt diet. Next, we examined the long-term effects of RLX treatment for 6 weeks on renal histology and transforming growth factor-beta1 (TGF-β1) expression in male DS and DR rats placed on the 8-week high-salt diet. RESULTS The short-term RLX treatment significantly attenuated the high-salt diet-induced rise in BP in DS rats with increasing neuronal NOS and endothelial NOS protein in kidneys. Selective inhibition of each of the three NOS isoforms significantly blocked the anti-hypertensive effects of RLX in DS rats after 1-week high-salt diet. The long-term treatment of DS rats with RLX for 6 weeks significantly reduced systolic BP, lessened glomerular and tubulointerstitial changes and reduced TGF-β signaling compared to saline-treated controls. CONCLUSIONS The results suggested that RLX converted salt sensitivity to salt resistance, at least in part, by up-regulating NOS. RLX is a potentially useful therapeutic agent for salt-sensitive hypertension.

Coenzyme Q10 Administration Suppresses both Oxidative and Antioxidative Markers in Hemodialysis Patients

Background: Increased oxidative stress is associated with various complications in hemodialysis (HD) patients. Methods: We examined the effect of coenzyme Q10 (CoQ10) administration on the plasma oxidative products and antioxidant capacity in 36 HD patients for 6 months. Results: The advanced oxidation protein products (AOPP), malondialdehyde and the percentage of ubiquinone in total CoQ10 were significantly higher in HD patients than in healthy subjects before administration (0 month). Oxygen radical absorbing capacity (ORAC) and Trolox equivalent antioxidant capacity (TEAC), indicators of total antioxidant capacity, were also paradoxically higher in the HD patients at 0 month. AOPP and the percentage of ubiquinone significantly decreased during CoQ10 administration, but increased again after the discontinuation. ORAC and TEAC were also decreased during CoQ10 administration. Conclusion: The CoQ10 administration was partially effective for suppressing the oxidative stress in HD patients. The unexpected decrease of ORAC and TEAC by CoQ10 seemed to be associated with a decreased oxidative stress.

The contribution of nitric oxide to renal vascular wall thickening in rats with l-NAME-induced hypertension

Abstract We investigated the mechanisms of renal vascular wall thickening in a rat model of N-nitro L-arginine methyl ester (L-NAME)-induced hypertension. To separate the effects of L-NAME-induced hypertension from other effects of nitric oxide (NO) inhibition, we created two models of L-NAME-induced hypertension: both had the same blood pressure level but NO inhibition was moderate in one group (group M) and severe in the other (group S). Urinary excretion of nitrates and nitrites was lower in group S than in group M. Wall thickening and lipid deposition in renal vessels were significantly greater in group S than in groups M. Simple and multiple regression analyses indicated that renal vascular wall thickening was more strongly correlated with lipid deposition than with blood pressure. The number of vessels positive for staining with Sudan black B was negatively correlated with urinary NO excretion. Expression of fibronectin and transforming growth factor-β was greater in the Sudan black B-positive than in the Sudan black B-negative vessels, suggesting that extracellular matrix production was increased in vessels with lipid deposition. Lipid deposition and increased production of extracellular matrix may contribute to renal vascular wall thickening in L-NAME-induced hypertension. Some mechanisms independent of hypertension play important roles in vascular wall thickening induced by NO inhibition.

Attenuation of the activated mammalian target of rapamycin pathway might be associated with renal function reserve by a low-protein diet in the rat remnant kidney model

The mammalian target of rapamycin (mTOR), a regulator of cellular protein synthesis and cell growth, plays an important role in the progression of renal hypertrophy and renal dysfunction in experimental chronic kidney disease models. Because the mTOR activity is regulated by nutrients including amino acids, we tested the hypothesis that the renoprotective effect of a low-protein diet (LPD) might be associated with the attenuation of the renal mTOR pathway. In this study, 5/6 nephrectomized rats were fed an LPD or a normal protein diet (NPD), and a number of rats that were fed an NPD received rapamycin (1.0 mg kg⁻¹ d⁻¹), a specific inhibitor of mTOR. After 6 weeks, renal tissue was collected to evaluate the activity of the mTOR pathway and histologic changes. The phosphorylation of p70S6k, a kinase in the downstream of mTOR, was significantly higher in the NPD-fed rats that showed progressive renal dysfunction than in the sham-operated rats (NPD). The LPD attenuated the excessive phosphorylation of p70S6k concomitant with reduced proteinuria and improved renal histologic changes in the 5/6 nephrectomized rats. The effects of the LPD were similar to the effects of rapamycin. The expression of phosphorylated p70S6k was significantly correlated with proteinuria (r² = 0.63, P < .001), the glomerular area (r² = 0.60, P < .001), and the number of phosphorylated Smad2-positive cells in the glomerulus (r² = 0.26, P < .05) of these rats. These results suggest that the preventive effect of an LPD on the progression of renal failure is associated with attenuation of the activated mTOR/p70S6k pathway in the rat remnant kidney model.