Renal Cyclooxygenase Products are Higher and Lipoxygenase Products are Lower in Early Disease in the pcy Mouse Model of Adolescent Nephronophthisis

Abstract

Nephronophthisis (NPHP) is a pediatric form of hereditary polycystic kidney disease (PKD), and is the leading cause of end stage renal disease in children. The pcy mouse is an orthologous model of human NPHP, with a mutation in the Nphp3 gene. Renal phospholipase A2, cyclooxygenase (COX) 1 and cyclic AMP are elevated in this model, suggesting that eicosanoid formation may be altered. In another type of PKD observed in the Han:SPRD-Cy rat, inhibition of eicosanoid production slows disease progression. If renal eicosanoids are similarly altered in NPHP, potential for pharmacologic intervention also may exist for this disorder. Therefore, renal fatty acids and eicosanoids were determined in pcy and normal mice at 15, 30 and 60 days of age by gas chromatography and HPLC-tandem mass spectrometry, respectively. Renal cysts in enlarged kidneys were observed in pcy mice by 15 days of age and increased over time. Renal phospholipid ARA levels were higher in pcy compared to normal mice at 15 and 30 days. Eicosanoid differences were observed starting at 30 days, when the COX products 6-keto-prostaglandin (PG) F1α, thromboxane B2 and PGE2 were higher in pcy compared to normal kidneys. Overall, total COX products were elevated at 30 and 60 days. In contrast, the levels of the lipoxygenase (LOX) products were not altered until 60 days of age and these were lower in pcy kidneys compared to normal. These findings suggest that altered eicosanoids play a role in NPHP, and that manipulating these levels with pharmacologic agents may have therapeutic potential.

Dietary flax oil rich in α-linolenic acid reduces renal disease and oxylipin abnormalities, including formation of docosahexaenoic acid derived oxylipins in the CD1-pcy/pcy mouse model of nephronophthisis

“…Kidney COX derived oxylipins are up-regulated in the pcy mouse model by as early as 30 days of age [7]. A similar elevation of renal COX oxylipins is observed in the Han:SPRD-Cy rat, a related model of slowly progressive kidney cyst formation [21,25], and reduction of COX oxylipins via pharmacological or dietary interventions have been shown to reduce disease progression [21,[26][27][28].…”

“…Our previous studies on the pcy mouse, as well as on a related model of cystic kidney disease (the Han:SPRDCy rat), revealed that cytosolic phospholipase A 2 and COX protein levels are altered in diseased cystic kidneys [6]. Further studies showed that COX products from arachidonic acid (AA) are elevated and LOX products from both AA and linoleic acid (LA) are lower in pcy mouse kidneys compared to those of normal kidneys as early as 30 days of age [7]. Renal COX products such as PGI 2, PGE 2 and PGD 2 may play a role in the development of cystic disease, as they increase renal cAMP [8], which is elevated in kidney, cyst fluid and urine of pcy mice as young as 45-70 days of age [9].…”

Linoleic acid derived oxylipins are elevated in kidney and liver and reduced in serum in rats given a high-protein diet

“…TXA2 stimulates cell proliferation in culture, and is a potent vasoconstrictor. In addition, TXA2 synthase inhibitors reduce progressive glomerular destruction in rat kidneys [134,135]. Another oxylipin, 20-HETE, produced from AA is an effective vasoconstrictor and mediates inflammation [136].…”

Prostaglandin E1 as therapeutic molecule for Nephronophthisis and related ciliopathies

“…Dysregulation of cAMP signaling is a common feature of CKD. In ADPKD and infantile NPH mouse models, renal cAMP levels are increased and associated with increased proliferation and cyst formation (43,44). In contrast, cAMP signaling cascade is decreased in several models of renal fibrosis (45).…”