Contribution of prostaglandin D2 synthase to progression of renal failure and dialysis dementia.
This article reviews the possible role of prostaglandin D(2) synthase (PGD(2)S) in the progression of chronic renal failure and dialysis dementia. Such a proposal is based on our observation that PGD(2)S significantly increases the rate of apoptosis in cultured pig kidney proximal tubule LLC-PK1 and rat neuronal PC12 cells. Apoptosis was caspase mediated and inhibitable by PGE(1), PGE(2), PGF(2alpha), platelet-derived growth factor (PDGF), and by PGD(2)S inhibitors, selenium and anti-PGD(2)S antibody. Apoptosis was restored by the addition of downstream metabolic products, PGD(2) and 15 deoxy PG triangle up (12,14)J(2). The proposal that PGD(2)S contributes to progression of renal failure and dialysis dementia is based on: (1) the progressive creatinine-like increase in PGD(2)S levels in blood as renal function decreases, increased renal cyclooxygenase (COX) 2 in chronic renal failure, and reported increase in apoptosis noted in the remnant kidney model, and (2) a 35- to 150-fold increase in blood levels of PGD(2)S in dialysis patients. Both conditions appear to favor shifting the PG metabolic pathway to downstream apoptotic metabolites, PGD(2) and 15 deoxy PG triangle up (12,14)J(2). The diverse role that PGs, growth factors, and COX play in progression of chronic renal failure, their interactions with PGD(2)S, and the status of COX inhibitors in retarding the progression of renal failure are reviewed. In addition, the need for a more systematic longitudinal assessment of dementia in dialysis patients by standardized neuropsychologic testing, testing blood levels and glycosylated isoforms of PGD(2)S, and the effect of COX inhibition and erythropoietin administration on dialysis dementia are discussed.
Maesaka
John K
JK
Department of Medicine, Division of Nephrology and Hypertension, Winthrop-University Hospital, Mineola, NY 11501, USA. jmaesaka@winthrop.org
Palaia
Thomas
T
Fishbane
Steven
S
Ragolia
Louis
L
D000818:Animals; D002908:Chronic Disease; D003704:Dementia / Q000209:etiology* / Q000503:physiopathology* / Q000628:therapy; D018450:Disease Progression; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D054834:Lipocalins; D006435:Renal Dialysis / Q000009:adverse effects*; D051437:Renal Insufficiency / Q000150:complications / Q000503:physiopathology* / Q000628:therapy*
D054834:Lipocalins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase