Publications

1. Hu, M. C., et al. (2016). "Renal Production, Uptake, and Handling of Circulating alphaKlotho." J Am Soc Nephrol 27(1): 79-90. PMID: 25977312

ABSTRACT: αKlotho is a multifunctional protein highly expressed in the kidney. Soluble αKlotho is released through cleavage of the extracellular domain from membrane αKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating αKlotho production and handling is incompletely understood, however. Here, we found higher αKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum αKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of αKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous αKlotho in anephric rats was four- to five-fold longer than that in normal rats, and exogenously injected labeled recombinant αKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that αKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in αKlotho homeostasis, producing and releasing αKlotho into the circulation and clearing αKlotho from the blood into the urinary lumen.

2. Inrig, J. K., et al. (2011). "Intradialytic hypertension and its association with endothelial cell dysfunction." Clin J Am Soc Nephrol 6(8): 2016-2024. PMID: 21757643

BACKGROUND AND OBJECTIVES: Intradialytic hypertension is associated with adverse outcomes, yet the mechanism is uncertain. Patients with intradialytic hypertension exhibit imbalances in endothelial-derived vasoregulators nitric oxide and endothelin-1, indirectly suggesting endothelial cell dysfunction. We hypothesized that intradialytic hypertension is associated in vivo with endothelial cell dysfunction, a novel predictor of adverse cardiovascular outcomes.
DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: We performed a case-control cohort study including 25 hemodialysis (HD) subjects without (controls) and 25 with intradialytic hypertension (an increase in systolic BP pre- to postdialysis >/=10 mmHg >/=4/6 consecutive HD sessions). The primary outcome was peripheral blood endothelial progenitor cells (EPCs) assessed by aldehyde dehydrogenase activity (ALDH(br)) and cell surface marker expression (CD34(+)CD133(+)). We also assessed endothelial function by ultrasonographic measurement of brachial artery flow-mediated vasodilation (FMD) normalized for shear stress. Parametric and nonparametric tests were used to compare EPCs, FMD, and BP.
RESULTS: Baseline characteristics and comorbidities were similar between groups. Compared with controls, 2-week average predialysis systolic BP was lower among subjects with intradialytic hypertension (144.0 versus 155.5 mmHg), but postdialysis systolic BP was significantly higher (159.0 versus 128.1 mmHg). Endothelial cell function was impaired among subjects with intradialytic hypertension as measured by decreased median ALDH(br) cells and decreased CD34(+)CD133(+) cells (ALDH(br), 0.034% versus 0.053%; CD34(+)CD133(+), 0.033% versus 0.059%). FMD was lower among subjects with intradialytic hypertension (1.03% versus 1.67%).
CONCLUSIONS: Intradialytic hypertension is associated with endothelial cell dysfunction. We propose that endothelial cell dysfunction may partially explain the higher event rates observed in these patients.

3. Jain, N., et al. (2016). "Differences in Whole Blood Platelet Aggregation at Baseline and in Response to Aspirin and Aspirin Plus Clopidogrel in Patients With Versus Without Chronic Kidney Disease." Am J Cardiol 117(4): 656-663. PMID: 26725101

ABSTRACT: Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16 non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome was residual platelet aggregability (RPA; proportion with < 50% IPA). Baseline platelet aggregability was similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Omega;, p = 0.007. CKD versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p = 0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19 polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms.

4. Neyra, J. A., et al. (2016). "The authors reply." Crit Care Med 44(1): e53-54. PMID: 26672946

5. Umetani, M. (2016). "Re-adopting classical nuclear receptors by cholesterol metabolites." J Steroid Biochem Mol Biol 157: 20-26. PMID: 26563834

ABSTRACT: Since the first cloning of the human estrogen receptor (ER) α in 1986 and the subsequent cloning of human ERβ, there has been extensive investigation of the role of estrogen/ER. Estrogens/ER play important roles not only in sexual development and reproduction but also in a variety of other functions in multiple tissues. Selective Estrogen Receptor Modulators (SERMs) are ER ligends that act as agonists or antagonists depending on the target genes and tissues, and until recently, only synthetic SERMs have been recognized. However, the discovery of the first endogenous SERM, 27-hydroxycholesterol (27HC), opened a new dimension of ER action in health and disease. In addition to the identification of 27HC as a SERM, oxysterols have been recently demonstrated as indirect modulators of ER through interaction with the nuclear receptor Liver X Receptor (LXR) β. In this review, the recent progress on these novel roles of oxysterols in ER modulation is summarized.