Enhanced Urinary Excretion of Eicosanoids in Fawn-Hooded Rats

Abstract

Compared to Wistar (WAG) rats, rats of the fawn-hooded (FH) strain have a high level of glomerular filtration rate (GFR) and urinary protein excretion (UpV). To investigate the possible role of vasoactive eicosanoids in this spontaneous model of hyperfiltration and proteinuria, we compared the urinary excretion of thromboxane-B₂ (T_xB₂), 6-keto-prostaglandin (Pg)F_1α and PgE₂ in male FH and WAG rats during normal ageing. All measurements were performed sequentially in the same animals 12, 24, 36, 48 and 60 weeks after weaning. Throughout the study, GFR was higher in FH rats as were the filtration fraction and UpV. From week 24, UpV in FH rats increased progressively. No elevations in UpV were observed in WAG rats. At weeks 12 and 24, the urinary excretion of TxB₂, 6-keto-PgF_1α and PgE₂ was 2-4 times higher in FH rats compared to WAG rats. With time, a shift in the urinary excretion from vasodilator to vasoconstrictor eicosanoids was observed, i.e., the excretion of PgE₂ declined and that of T_xB₂ increased. Proteinuria in FH rats was positively correlated with TxB₂ excretion and negatively correlated with PgE₂ excretion. We conclude that in FH rats, early hyperfiltration coincides with enhanced urinary excretion of all eicosanoids. Subsequent progressive proteinuria is associated with an increase in TxB₂ and a decrease in PgE₂ excretion.

Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats

“…7,31,and 34). Release of these substances would be in line with previous findings in FHH on enhanced excretion of all eicosanoids, including PGE 2 , coincident with the onset of hyperfiltration (14), whereas subsequent progressive proteinuria in these rats was associated with an increase in thromboxane B 2 and a decrease in PGE 2 excretion. Although the array of prostanoids produced by the MD has not been characterized, the primary product synthesized by the TAL is PGE 2 (4), which in the setting of volume depletion appears to maintain GFR by dilating the afferent arteriole (20).…”

“…It has further been suggested that COX-2 function is under the control of NO and is negatively regulated by angiotensin II (9,10). In FHH, increased urinary levels of various eicosanoids have previously been reported to coincide with hyperfiltration (14).…”

Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat

“…The primary mechanism underlying endothelial dysfunction in renal arteries of FHH rats is COX-1-mediated endothelium-dependent contraction resulting from excessive production of vasoconstrictive endoperoxides and/or TXs and superoxide radical. Interestingly, early hyperfiltration in FHH rats was reported to coincide with an excessive urinary excretion of contractile PGs (15), suggesting the role of PGs in the development of spontaneous renal injury. However, alternatively, COX-mediated renal endothelial dysfunction may be associated with the development of spontaneous hypertension (30), since it is present at an early, prehypertensive stage in the spontaneously hypertensive rat (2), possibly being a hypertension-driven renal disease as apposed to a renally initiated hypertension in FHH.…”

“…Only few studies reported heterogeneity of myogenic mechanisms among vascular beds (15), and differential mechanisms have not been characterized yet. Several mechanosensitive ion channels and integrins may be involved in a stretch-induced mechanotransduction, whereas other factors have been implicated in the myogenic signal transduction, including activation of the calmodulin/myosin light chain kinase pathway, protein kinase C, mitogen-activated protein kinases, several potassium channels, and cytochrome P-450-derived metabolites of arachidonic acid (20-HETE, EETs), the latter being EDHF in the renal vasculature (30).…”