A klotho gene single nucleotide polymorphism is associated with the onset of stroke and plasma klotho concentration.

Klotho protects against development of multiple age-related disorders, including cardiovascular diseases. We assessed whether a human klotho single nucleotide polymorphism (SNP) rs650439 is associated with the onset of stroke in hypertensive patients and plasma klotho concentration in the general population. Five hundred and twenty-three patients with hypertension were analyzed for both the presence of rs650439 and onset of stroke. We found that hypertensive patients with the TT genotype of rs650439 (n=52) had a higher incidence of stroke than those with AT (n=257) and AA (n=214) genotypes. Multivariate analysis indicated that the TT genotype was the only risk factor associated with increased incidence of stroke. Plasma klotho concentrations were measured in a general population (age=70±1 years) to assess the association between rs650439 and plasma klotho concentration. A significant trend was observed in the elderly population where plasma klotho concentration decreased as the T alleles in rs650439 increased. Subjects with a TT genotype had lower plasma klotho concentrations than those with AT+AA genotypes. In conclusion, TT genotype of klotho SNP (rs650439) is correlated with an increased incidence of stroke in hypertensive patients, and the mechanism underlying this correlation might involve the effect of rs650439 T allele on plasma klotho concentrations.

Relationship between renal hemodynamic status and aging in patients without diabetes evaluated by renal Doppler ultrasonography.

BACKGROUND: Aging is well known as one of the major causes of a reduced glomerular filtration rate (GFR). The resistive index (RI) measured by renal Doppler ultrasonography (RDU) is thought to be a good indicator of renal vascular resistance induced by arteriosclerosis. In this study, we investigated whether RI could be used to evaluate the pathogenesis of renal damage or the mechanisms of reduction of renal function by aging. METHODS: We investigated the correlation between RI and multiple clinical parameters and the influence of aging on the renal hemodynamic status of 194 in-patients (mean age 66.2 years) who underwent RDU at our hospital between February 2009 and July 2010. RESULTS: RI was significantly correlated with the age, estimated GFR (eGFR), diastolic blood pressure, pulse pressure, and degree of albuminuria. Subjects aged ≥75 years showed a significantly higher correlation coefficient between eGFR and RI. RI showed a stronger correlation with age in subjects aged ≥75 years compared to eGFR. CONCLUSION: The present study showed that renal vascular resistance and intra-renal arteriosclerosis had a greater impact on renal function in older than younger subjects, reflecting the possible mechanisms of renal function reduction due to aging.

Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway.

AIM: Mice that carry the Klotho mutation (KL(-) (/) (-) ) manifest diverse age-related disorders similar to those observed in humans. Thus, the Klotho protein might function as an anti-aging hormone in mammals. Recently, we reported that Klotho recombinant protein attenuated apoptosis and cellular senescence in endothelial cells, but the mechanism remained unclear. Here, we designed an in vitro study to test whether inhibitors of extracellular signal-regulated kinase and mitogen-activated kinase kinase could affect Klotho regulation of apoptosis and cellular senescence. METHODS: Cellular senescence was investigated in human umbilical vein endothelial cells treated with or without Klotho recombinant protein, and with or without inhibitors of mitogen-activated kinases. Senescence was quantified by staining with senescence-associated ß-galactosidase and by evaluating western blots probed for phosphorylation of mitogen-activated kinases. Apoptosis was assayed on western probed for p53, p21, and caspase-3 and -9. RESULTS: The Klotho recombinant protein induced transient phosphorylation of mitogen-activated kinases within a few minutes. Application of inhibitors of mitogen-activated kinases attenuated the ability of Klotho to interfere with apoptosis and senescence in endothelial cells. CONCLUSION: This study demonstrated that Klotho attenuated cellular apoptosis and senescence in vascular cells via mitogen-activated kinase kinase and extracellular signal-regulated kinase pathways.

Usefulness of the resistive index in renal Doppler ultrasonography as an indicator of vascular damage in patients with risks of atherosclerosis.

BACKGROUND: Chronic kidney disease (CKD) is caused by various risk factors of cardiovascular disease (CVD). The estimated glomerular filtration rate (eGFR) is commonly used for the evaluation of the renal function in patients with CKD; however, it is difficult to assess the pathogenesis of CKD and predict the renal prognosis accurately using only eGFR. The resistive index (RI) in renal Doppler ultrasonography (RDU) is thought to be a good indicator of renal vascular resistance caused by atherosclerosis. In the present study, we investigated whether RI could be used to evaluate the pathogenesis of renal damage and predict the renal prognosis and investigated the correlation between RI and blood pressure (BP) fluctuations in patients with or without hypertension. METHODS: The total study population included 194 patients (mean age: 66.2 years), who underwent RDU in our hospital ward between February 2009 and July 2010. We investigated the correlation between RI and multiple clinical parameters, including ambulatory blood pressure monitoring (ABPM). RESULTS: RI significantly correlated with age, eGFR, diastolic BP, pulse pressure and level of albuminuria. Patients with diabetes mellitus (DM) showed a significantly higher RI than patients without DM, although their eGFR was similar; thus, DM might accelerate renal vascular damage and RI could detect earlier changes of vascular damage proceeding the time eGFR is reduced. Regarding ABPM, patients with a larger morning surge [systolic blood pressure (SBP) in the early morning--lowest SBP during sleep] showed a significantly higher RI. CONCLUSIONS: The present study indicated that RI might be very useful for the evaluation of very early renal damage more effectively than eGFR and that diurnal BP change might be partly due to the progression of atherosclerotic change in the kidney evaluated by RI.