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West R.K.,Mount Sinai School of Medicine | Moshier E.,Mount Sinai School of Medicine | Lubitz I.,The Sheba Medical Center | Schmeidler J.,Mount Sinai School of Medicine | And 8 more authors.
Mechanisms of Ageing and Development | Year: 2014

We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p= 0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors). Since modifying the levels of AGEs in the diet may be relatively easy, these preliminary results suggest a simple strategy to diminish cognitive compromise in the elderly and warrant further investigation. © 2014 Elsevier Ireland Ltd.

Liu Y.,Mount Sinai School of Medicine | Flores D.,Mount Sinai School of Medicine | Flores D.,The James ters Veterans Affairs Medical Center | Carrisoza-Gaytan R.,Mount Sinai School of Medicine | And 2 more authors.
American Journal of Physiology - Renal Physiology | Year: 2014

High-dietary sodium (Na), a feature of the Western diet, requires the kidney to excrete ample Na to maintain homeostasis and prevent hypertension. High urinary flow rate, presumably, leads to an increase in fluid shear stress (FSS) and FSS-mediated release of prostaglandin E2 (PGE2) by the cortical collecting duct (CCD) that enhances renal Na excretion. The pathways by which tubular flow biomechanically regulates PGE2 release and cyclooxygenase-2 (COX-2) expression are limited. We hypothesized that FSS, through stimulation of neutral-sphingomyeli-nase (N-SM) activity, enhances COX-2 expression to boost Na excretion. To test this, inner medullary CD3 cells were exposed to FSS in vitro and mice were injected with isotonic saline in vivo to induce high tubular flow. In vitro, FSS induced N-SM activity and COX-2 protein expression in cells while inhibition of N-SM activity repressed FSS-induced COX-2 protein abundance. Moreover, the murine CCD expresses N-SM protein and, when mice are injected with isotonic saline to induce high tubular flow, renal immunodetectable COX-2 is induced. Urinary PGE2 (445 ± 91 vs. 205 ± 14 pg/ml; P < 0.05) and microdissected CCDs (135.8 ± 21.7 vs. 65.8 ± 11.0 pg·ml_1·mm-1 CCD; P < 0.05) from saline-injected mice generate more PGE2 than sham-injected controls, respectively. Incubation of CCDs with arachi-donic acid and subsequent measurement of secreted PGE2 are a reflection of the PGE2 generating potential of the epithelia. CCDs isolated from polyuric mice doubled their PGE2 generating potential and this was due to induction of COX-2 activity/protein. Thus, high tubular flow and FSS induce COX-2 protein/activity to enhance PGE2 release and, presumably, effectuate Na excretion.

Liu Y.,Mount Sinai School of Medicine | Liu Y.,The James ters Veterans Affairs Medical Center | Flores D.,Mount Sinai School of Medicine | Flores D.,The James ters Veterans Affairs Medical Center | And 3 more authors.
American Journal of Physiology - Renal Physiology | Year: 2015

Essential hypertension (eHTN) is associated with hypercholesterolemia, but how cholesterol contributes to eHTN is unknown. Recent evidence demonstrates that short-term dietary cholesterol ingestion induces epithelial Na channel (ENaC)- dependent Na absorption with a subsequent rise in blood pressure (BP), implicating cholesterol in salt-sensitive HTN. Prostaglandin E2 (PGE2), an autocrine/paracrine molecule, is induced by flow in endothelia to vasodilate the vasculature and inhibit ENaC-dependent Na absorption in the renal collecting duct (CD), which reduce BP. We hypothesize that cholesterol suppresses flow-mediated cyclooxygenase- 2 (COX-2) expression and PGE2 release in the CD, which, in turn, affects Na absorption. Cortical CDs (CCDs) were microperfused at 0, 1, and 5 nl·min-1·mm-1, and PGE2 release was measured. Secreted PGE2 was similar between no- and low-flow (151 ± 28 vs. 121 ± 48 pg·ml-1·mm-1) CCDs, but PGE2 was greatest from high-flow (578 ± 146 pg·ml-1·mm-1; P < 0.05) CCDs. Next, mice were fed either a 0 or 1% cholesterol diet, injected with saline to generate high urine flow rates, and CCDs were microdissected for PGE2 secretion. CCDs isolated from cholesterol-fed mice secreted less PGE2 and had a lower PGE2-generating capacity than CCDs isolated from control mice, implying cholesterol repressed flow-induced PGE2 synthesis. Next, cholesterol extraction in a CD cell line induced COX-2 expression and PGE2 release while cholesterol incorporation, conversely, suppressed their expression. Moreover, fluid shear stress (FSS) and cholesterol extraction induced COX-2 protein abundance via p38-dependent activation. Thus cellular cholesterol composition affects biomechanical signaling, which, in turn, affects FSS-mediated COX-2 expression and PGE2 release via a p38-dependent mechanism. © 2015 the American Physiological Society.

Flores D.,Mount Sinai School of Medicine | Flores D.,The James ters Veterans Affairs Medical Center | Liu Y.,Mount Sinai School of Medicine | Liu Y.,The James ters Veterans Affairs Medical Center | And 4 more authors.
American Journal of Physiology - Renal Physiology | Year: 2012

Fluid shear stress (FSS) is a critical regulator of cation transport in the collecting duct (CD). High-dietary sodium (Na) consumption increases urine flow, Na excretion, and prostaglandin E2 (PGE2) excretion. We hypothesize that increases in FSS elicited by increasing tubular flow rate induce the release of PGE2 from renal epithelial cells into the extracellular compartment and regulate ion transport. Media retrieved from CD cells exposed to physiologic levels of FSS reveal several fold higher concentration of PGE2 compared with static controls. Treatment of CD cells with either cyclooxygenase-1 (COX-1) or COX-2 inhibitors during exposure to FSS limited the increase in PGE2 concentration to an equal extent, suggesting COX-1 and COX-2 contribute equally to FSS-induced PGE2 release. Cytosolic phospholipase A2 (cPLA2), the principal enzyme that generates the COX substrate arachidonic acid, is regulated by mitogen-activated proteinkinase-dependent phosphorylation and intracellular Ca2+ concentration ([Ca2+]i), both signaling processes, of which, are activated by FSS. Inhibition of the ERK and p38 pathways reduced PGE2 release by 53.3 ± 8.4 and 32.6 ± 11.3%, respectively, while antagonizing the JNK pathway had no effect. In addition, chelation of [Ca2+]i limited the FSS-mediated increase in PGE2 concentration by 47.5 ± 7.5% of that observed in untreated sheared cells. Sheared cells expressed greater phospho-cPLA2 protein abundance than static cells; however, COX-2 protein expression was unaffected (P = 0.064) by FSS. In microperfused CDs, COX inhibition enhanced flow-stimulated Na reabsorption and abolished flow-stimulated potassium (K) secretion, but did not affect ion transport at a slow flow rate, implicating that high tubular flow activates autocrine/paracrine PGE2 release and, in turn, regulates flow-stimulated cation transport. In conclusion, FSS activates cPLA2 to generate PGE2 that regulates flow-mediated Na and K transport in the native CD. We speculate that dietary sodium intake modulates tubular flow rate to regulate paracrine PGE2 release and cation transport in the CD.

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