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Background and Aims A recent study demonstrated female rats more rapidly excreted urine sodium and water under saline bolus infusion than male rats, and suggested sexual dimorphisms in renal transporters. However, the sexual differences in renal salt and water excretion was not yet investigated with human data. We purposed to clarify whether the sexual difference of natriuretic and diuretic ability exists, and it contributes to decreasing blood pressure (BP) in nondiabetic chronic kidney disease (CKD) patients. Method This is a secondary analysis of an open-label, randomized, controlled study determining the effect of intensive low-salt diet education on BP and albuminuria in nondiabetic CKD patients. A total of 235 patients had stopped all renin-angiotensin blocking agents or diuretics during a run-in period for eight weeks (0w). After the run-in period, they received olmesartan (40mg daily) for eight weeks (8w), and then maintained the same medicine with low-salt diet education for an additional eight weeks (16w). Results Mean age of premenopausal women (n=50), same-aged young men (n=76), postmenopausal women (n=68), and same-aged older men (n=41) was 40.7, 40.2, 59.0, and 69.9 years old, respectively. Their MDRD eGFR was 76.2, 71.6, 59.8, and 58.8 mL/min/1.73m2, respectively. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was lower in premenopausal women (129/79 mmHg) than in young men (134/83 mmHg). Daily salt intake decreased in 16w in premenopausal women (1839 → 1288mg, p=0.008) and young men (2494 → 1552mg, p=0.001) compared with them in 0w, while there was no significant change in postmenopausal women (2443 → 2171mg, p=0.610) and older men (2870 → 2366mg, p=0.458). Except for the premenopausal women (136 (0w) → 133 (16w) mEq/day, p=0.749), urine sodium excretion for 24 hours significantly decreased in 16w compared with that in 0w or 8w (young men: 154 (8w) → 137 (16w)mEq/day p=0.042, postmenopausal women: 152 (0w) → 128m (16w)Eq/day p=0.016, older men: 181 (0w) → 145 (16w)mEq/day p=0.019). Also, urine volume was significantly larger in the premenopausal women than in young men in 8w and 16w (8w: 1009 vs. 980mL p=0.002, 16w: 1004 vs. 978mL, p=0.006), while it was not different between postmenopausal women and older men (8w: 1002 vs. 990 p=0.347, 16w: 1003 vs. 1001 p=0.895). The urine volume was positively correlated with BP in the premenopausal women, while it was negatively associated with BP in young men in 16w. Conclusion Although sodium intake was similarly decreased in premenopausal women and young men, urine sodium excretion did not fall, and urine volume increased in premenopausal women. This phenomenon disappeared in postmenopausal women. Augmented natriuretic and diuretic potency might contribute to lower BP in premenopausal women with nondiabetic CKD.

Background. The peroxisome proliferator-activated receptor-a (PPARa) is a lipid-sensing transcriptional factor that has a role in gluco-oxidative stress and lipotoxicity. Forkhead box O (FoxO)s and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1a are also known to regulate cell metabolism, cell cycle arrest, apoptosis and oxidative stress during stressful conditions. We evaluated whether PPARa–FoxOs–PGC-1a signaling in overfed spontaneously hypertensive rats (SHR) has a protective role in the kidney. Methods. Male SHR and Wistar–Kyoto rats (WKY) fed a high-fat diet (HFD) received treatment with fenofibrate, PPARa agonist or tempol, antioxidants for 12 weeks and were evaluated about the PPARa–FoxOs–PGC-1a pathway. Results. The SHRs with an HFD had an elevated systolic pressure, plasma insulin, free fatty acid (FFA) and triglyceride (TGs) levels, and they had induced glucose intolerance as well as albuminuria, glomerular expansion and renal inflammation. An HFD caused the accumulation of intra-renal FFA and TGs and this was related to a decrease in the PPARa expression, the activation of phosphatidylinositol 3-kinase (PI3K)–Akt, phosphorylation of FoxO3a and decreases in the PGC-1a and estrogen-related receptor (ERR)-1a expressions, which suppressed the superoxide dismutase (SOD2) and Bcl-2 expressions and led to increases in oxidative stress and the number of apoptotic renal cells. Interestingly, administering fenofibrate or tempol to the HFD-induced SHRs reversed all of the renal phenotypes by increasing the PPARa expression with concomitant inactivation of the PI3K–Akt pathway, dephosphorylation of FoxO3a and activation of PGC-1a–ERR-1a signaling, and this all resulted in ameliorating the oxidative stress and apoptotic cell death. Conclusion. Our results demonstrated that PPARa agonists or antioxidants are associated with improvement of the circulating FFA and TGs levels and this prevents HFDinduced renal lipotoxicity and hypertension by the activation of PPARa and its downstream signals of both FoxO3a and PGC-1a.

Background Obesity has been strongly associated with the development and aggravation of hypertension and chronic kidney disease. To date, the systemic renin-angiotensin system (RAS) has been known to involve in obesity-induced tissue damage and hypertension. However, the intrarenal mechanism whereby obesity induces and aggravates hypertension and renal disease remains poorly understood. Therefore, we investigated the role of intrarenal RAS and oxidative stress in diet-induced hypertension and renal inflammation in spontaneously hypertensive rats (SHR) fed a high-fat diet. Methods Male SHR and Wistar-Kyoto rats (WKY) were divided into eight groups: normal-fat diet-fed WKY (WKY-NF), high-fat diet-fed WKY (WKY-HF), high-fat diet-fed tempol-treated WKY (WKY-HF/T), high-fat diet-fed candesartan-treated WKY (WKY-HF/C), normal-fat diet-fed SHR (SHR-NF), high-fat diet-fed SHR (SHR-HF), high-fat diet-fed tempol-treated SHR (SHR-HF/T) and high-fat diet-fed candesartan-treated SHR (SHR-HF/C). After 12 weeks of treatment, haemodynamic measurements and histological assessment of the kidney were performed. Results At the end of week 12, the high-fat fed SHR gained more body weight, their systolic blood pressure was further elevated and glucose intolerance induced. There was no significant difference in the insulin resistance index, serum lipid profile, plasma renin activity and serum aldosterone levels according to diet. However, the high-fat diet resulted in increases in immunohistochemical stains of renin and angiotensin II in the kidney. The real-time PCR also demonstrated significant increases in mRNA levels of renin, angiotensinogen and angiotensin-converting enzyme in the kidney, reflecting enhanced activation of the intrarenal RAS, which findings were also shown by Western blot analysis for renin and angiotensin II type 1 receptor. The expression of ED-1, osteopontin and TGF-beta1 in the renal cortex were prominently enhanced in the SHR-HF group with the increased intrarenal lipid concentrations and oxidative stress. Administration of tempol or candesartan in the high-fat diet-induced SHR inhibited the elevation of the systolic blood pressure, intrarenal lipid concentrations, oxidative stress and the degree of renal inflammation to the levels of, or more than, the SHR-NF with no differences in the body weight and periepididymal fat weight, compared to those in the SHR-HF group without such treatment. Conclusions Our study suggests that a high-fat diet induces fatty kidneys, aggravation of blood pressure and renal inflammation in the SHR. Blockade of oxidative stress by tempol or of RAS by candesartan ameliorates the increase in blood pressure and renal inflammation and improves intrarenal lipid accumulation. Therefore, antioxidants or angiotensin receptor blockers can prevent diet-induced hypertension and renal inflammation in hypertensive rats.

Background and methods Tissue transglutaminase (tTG) may induce pro-inflammatory cytokines and produce irreversible end-products, thus promoting renal scarring. It has recently been confirmed that the crescent formation in murine experimental crescentic glomerulonephritis (ecGN) has been inhibited by the administration of recombinant uteroglobin (rUG). However, the ability of UG on tTG modulation has not been thoroughly assessed. In this study, we investigated the feasible protective role of UG in murine ecGN through the modulation of tTG and TGF-beta1 expressions. ecGN was induced by the administration of anti-GBM Ab into C57BL/6 mice. Results Both proteinuria and BUN levels were distinctively lower in rUG-treated mice compared to those of disease control mice. Glomerular injuries such as mesangial proliferation, matrix production and crescent formation were lessened with the rUG treatment, and these findings were parallel with the attenuated expression of tTG and TGF-beta1. tTG and TGF-beta1 were expressed mainly on mesangial areas by the induction of ecGN and rUG treatment markedly attenuated the expressions of these proteins in glomeruli without spatial changes. With the addition of LPS to mesangial cells, the expressions of tTG and TGF-beta1 were up-regulated, whilst the addition of cysteamine, tTG inhibitor, attenuated the expression of tTG and TGF-beta1 as well as the cellular proliferation which was further induced by LPS. Conclusion We demonstrate for the first time that rUG is able to attenuate the renal injury through the modulation of expressions of tTG and TGF-beta1 in ecGN and further suggest a wide range of feasible molecular targets to reduce the severity of human glomerulonephritis.