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Renal salt wasting without cerebral disease: diagnostic value of urate determinations in hyponatremia [Case Report]

Maesaka, J K; Miyawaki, N; Palaia, T; Fishbane, S; Durham, J H C
PMID: 17311074
ISSN: 0085-2538
CID: 3464682

Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice

Ragolia, Louis; Palaia, Thomas; Hall, Christopher E; Maesaka, John K; Eguchi, Naomi; Urade, Yoshihiro
Type 2 diabetics have an increased risk of developing atherosclerosis, suggesting the mechanisms that cause this disease are enhanced by insulin resistance. In this study we examined the effects of gene knock-out (KO) of lipocalin-type prostaglandin D(2) synthase (L-PGDS), a protein found at elevated levels in type 2 diabetics, on diet-induced glucose tolerance and atherosclerosis. Our results show that L-PGDS KO mice become glucose-in-tolerant and insulin-resistant at an accelerated rate when compared with the C57BL/6 control strain. Adipocytes were significantly larger in the L-PGDS KO mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls. In addition, only the L-PGDS KO mice developed nephropathy and an aortic thickening reminiscent to the early stages of atherosclerosis when fed a "diabetogenic" high fat diet. We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy.
PMID: 15970590
ISSN: 0021-9258
CID: 3464662

A patient with an uncommon etiology of intradialytic hypotension [Case Report]

Masani, Naveed N; Miyawaki, Nobuyuki; Maesaka, John K
Hemodialysis is associated with various complications, the most common being intradialytic hypotension (IDH). In the majority of cases, IDH is easily corrected and does not represent a life-threatening condition. We present a patient in whom IDH was unresponsive to various corrective strategies. A new mitral valve regurgitant lesion was diagnosed that eventually led to the patient's demise. Unusual etiologies of IDH need to be considered, particularly in instances where routine therapeutic measures are ineffective.
PMID: 16191186
ISSN: 0894-0959
CID: 3464672

Inhibition of cell cycle progression and migration of vascular smooth muscle cells by prostaglandin D2 synthase: resistance in diabetic Goto-Kakizaki rats

Ragolia, Louis; Palaia, Thomas; Koutrouby, Tara B; Maesaka, John K
The regulation of vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis plays a clear role in the atherosclerotic process. Recently, we reported on the inhibition of the exaggerated growth phenotype of VSMCs isolated from hypertensive rats by lipocalin-type prostaglandin D2 synthase (L-PGDS). In the present study, we report the differential effects of L-PGDS on VSMC cell cycle progression, migration, and apoptosis in wild-type VSMCs vs. those from a type 2 diabetic model. In wild-type VSMCs, exogenously added L-PGDS delayed serum-induced cell cycle progression from the G1 to S phase, as determined by gene array analysis and the decreased protein expressions of cyclin-dependent kinase-2, p21(Cip1), and cyclin D1. Cyclin D3 protein expression was unaffected by L-PGDS, although its gene expression was stimulated by L-PGDS in wild-type cells. In addition, platelet-derived growth factor-induced VSMC migration was inhibited by L-PGDS in wild-type cells. Type 2 diabetic VSMCs, however, were resistant to the L-PGDS effects on cell cycle progression and migration. L-PGDS did suppress the hyperproliferation of diabetic cells, albeit through a different mechanism, presumably involving the 2.5-fold increase in apoptosis and the concomitant 10-fold increase of L-PGDS uptake we observed in these cells. We propose that in wild-type VSMCs, L-PGDS retards cell cycle progression and migration, precluding hyperplasia of the tunica media, and that diabetic cells appear resistant to the inhibitory effects of L-PGDS, which consequently may help explain the increased atherosclerosis observed in diabetes.
PMID: 15240344
ISSN: 0363-6143
CID: 3464652

Platelet-derived growth factor-induced vascular smooth muscle cell migration is inhibited by prostaglandin D-2 synthase: Failure in the diabetic Goto-Kakizaki rat model [Meeting Abstract]

Ragolia, L; Palaia, T; Koutrouby, TB; Maesaka, JK
ISSN: 0012-1797
CID: 3464902

Cytoprotection by darbepoetin/epoetin alfa in pig tubular and mouse mesangial cells

Fishbane, Steven; Ragolia, Louis; Palaia, Thomas; Johnson, Barbra; Elzein, Hafez; Maesaka, John K
BACKGROUND:Erythropoietin has recently been found to have cytoprotective effects in the central nervous system (CNS) and retina. The purpose of this study was to determine if darbepoetin alfa (DA) has cytoprotective properties in renal tissues. METHODS:DA was studied in LLC/PK1 and mesangial cells. Renal cellular injury was induced in different experiments by prostaglandin D2 synthase (PGDS), camptothecin, hydrogen peroxide, and hypoxia. Cellular proliferation and apoptosis were measured [apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay or by caspase-3 activity]. In a separate experiment, an inactive form of erythropoietin alfa was used to study receptor effects. RESULTS:DA protected against the antiproliferative effects of PGDS. In both LLC/PK1 (TUNEL and caspase-3) and mesangial cells (TUNEL), DA reduced the apoptotic stimulus of PGDS. Epoetin alfa was also found to reduce apoptosis. In LLC/PK1 cells, DA reduced apoptosis induced by camptothecin, but not hydrogen peroxide. DA reduced LLC/PK1 apoptosis induced by hypoxia when added 24 hours before hypoxia, but not when given concurrent with the hypoxic stimulus. Erythropoietin inactive did not protect against PGDS-induced apoptosis. CONCLUSION/CONCLUSIONS:DA has renal antiapoptotic effects for both toxic and hypoxic stimuli. The effect may be mediated via the Erythropoietin receptor.
PMID: 14717915
ISSN: 0085-2538
CID: 3464642

Prostaglandin D2 synthase inhibits the exaggerated growth phenotype of spontaneously hypertensive rat vascular smooth muscle cells

Ragolia, Louis; Palaia, Thomas; Paric, Enesa; Maesaka, John K
Lipocalin-type prostaglandin D2 synthase (L-PGDS) has recently been linked to a variety of pathophysiological cardiovascular conditions including hypertension and diabetes. In this study, we report on the 50% increase in L-PGDS protein expression observed in vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR). L-PGDS expression also increased 50% upon the differentiation of normotensive control cells (WKY, from Wistar-Kyoto rats). In addition, we demonstrate differential effects of L-PGDS treatment on cell proliferation and apoptosis in VSMCs isolated from SHR versus WKY controls. L-PGDS (50 microg/ml) was able to significantly inhibit VSMC proliferation and DNA synthesis and induce the apoptotic genes bax, bcl-x, and ei24 in SHR but had no effect on WKY cells. Hyperglycemic conditions also had opposite effects, in which increased glucose concentrations (20 mm) resulted in decreased L-PGDS expression in control cells but actually stimulated L-PGDS expression in SHR. Furthermore, we examined the effect of L-PGDS incubation on insulin-stimulated Akt, glycogen synthase kinase-3beta (GSK-3beta), and ERK phosphorylation. Unexpectedly, we found that when WKY cells were pretreated with L-PGDS, insulin could actually induce apoptosis and failed to stimulate Akt/GSK-3beta phosphorylation. Insulin-stimulated ERK phosphorylation was unaffected by L-PGDS pretreatment in both cell lines. We propose that L-PGDS is involved in the balance of VSMC proliferation and apoptosis and in the increased expression observed in the hypertensive state is an attempt to maintain a proper equilibrium between the two processes via the induction of apoptosis and inhibition of cell proliferation.
PMID: 12684506
ISSN: 0021-9258
CID: 3464632

Elevated L-PGDS activity contributes to PMA-induced apoptosis concomitant with downregulation of PI3-K

Ragolia, Louis; Palaia, Thomas; Paric, Enesa; Maesaka, John K
Recently we demonstrated the induction of apoptosis by the addition of recombinant lipocalin-type prostaglandin D(2) synthase (L-PGDS) to the culture medium of LLC-PK(1) cells. Because protein kinase C (PKC) has been shown to be involved in the apoptotic process of various cell types, we examined the potential role of L-PGDS in phorbol 12-myristate 13-acetate (PMA)-induced apoptosis. We report here the enzymatic activation and phosphorylation of L-PGDS in response to phorbol ester in cell culture and the direct phosphorylation of recombinant L-PGDS by PKC in vitro. Treatment of cells with PMA or L-PGDS decreased phosphatidylinositol 3-kinase (PI3-K) activity and concomitantly inhibited protein kinase B (PKB/Akt) phosphorylation, which led to the hypophosphorylation and activation of Bad. In addition, hypophosphorylation of retinoblastoma protein was also observed in response to L-PGDS-induced apoptosis. Cellular depletion of L-PGDS levels by using an antisense RNA strategy prevented PI3-K inactivation by phorbol ester and inhibited caspase-3 activation and apoptosis. We conclude that phorbol ester-induced apoptosis is mediated by L-PGDS phosphorylation and activation by PKC and is accompanied by inhibition of the PI3-K/PKB anti-apoptotic signaling pathways.
PMID: 12388064
ISSN: 0363-6143
CID: 3465602

Treating interdialytic hyperkalemia with fludrocortisone [Editorial]

Imbriano, Louis J; Durham, John H; Maesaka, John K
Hyperkalemia is a frequent and dangerous problem in dialysis patients. Many factors contribute to potentially life-threatening potassium elevation and most remedies used to treat hyperkalemia are handicapped by the consequences of the separate pools of intra- and extracellular potassium. Besides the kidney, the colon has the ability to excrete potassium, which can help lower total body potassium. Several prior authors have addressed the colon's ability to up-regulate potassium secretion, including the effect of aldosterone on fecal potassium content. Potentially dangerous intradialytic maneuvers to lower potassium levels may be avoidable with the use of the mineralocorticoid agonist fludrocortisone.
PMID: 12535291
ISSN: 0894-0959
CID: 3464622

A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography

Durham, John D; Caputo, Christopher; Dokko, John; Zaharakis, Thomas; Pahlavan, Mohsen; Keltz, Jan; Dutka, Paula; Marzo, Kevin; Maesaka, John K; Fishbane, Steven
BACKGROUND:Contrast nephropathy (CN) is a common cause of renal dysfunction after cardiac angiography. Recently, N-acetylcysteine (NAC) has been found to reduce the risk of CN after CT imaging with contrast enhancement. The purpose of the current study was to evaluate the efficacy of NAC for the prevention of CN in the setting of cardiac angiography. METHODS:Eligible patients were those undergoing cardiac angiography with serum creatinine>1.7 mg/dL. Patients were randomized to one of two groups: Group 1, IV hydration and NAC, 1200 mg one hour before angiography, and a second dose 3 hours after; Group 2, IV hydration and placebo. CN was defined as an increase of 0.5 mg/dL in serum creatinine. RESULTS:Seventy-nine patients completed the study. There were no significant differences between the groups in baseline characteristics, duration of angiography, mean volume of dye infused or mean IV hydration. Contrast nephropathy developed in 24.0% of subjects, 26.3% NAC, and 22.0% placebo (P = NS). Among subjects with diabetes mellitus, there was no significant difference in the rate of CN between the groups (42.1% NAC, 27.8% placebo; P = 0.09). The independent predictors of CN risk were diabetes mellitus and preexisting chronic renal insufficiency. CONCLUSIONS:NAC was not effective for the prevention of CN after cardiac angiography.
PMID: 12427146
ISSN: 0085-2538
CID: 3444182