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Cyclooxygenase Metabolites in the Kidney

Raymond C. Harris, Ming‐Zhi Zhang

10.1002/cphy.c100077

Source: Volume 1, Issue 4, October 2011

Published online: October 2011

Full Article on Wiley Online Library



Abstract

In the mammalian kidney, prostaglandins (PGs) are important mediators of physiologic processes, including modulation of vascular tone and salt and water. PGs arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of AA in the kidney. COX are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by PG and thromboxane synthases. In addition to high levels of expression of the “constitutive” rate‐limiting enzyme responsible for prostanoid production, COX‐1, the “inducible” isoform of cyclooxygenase, COX‐2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. PGs and thromboxane A2 exert their biological functions predominantly through activation of specific 7‐transmembrane G‐protein‐coupled receptors. COX metabolites have been shown to exert important physiologic functions in maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also seen in a variety of inflammatory renal injuries, and COX metabolites may serve as mediators of inflammatory injury in renal disease. © 2011 American Physiological Society. Compr Physiol 1:1729‐1758, 2011.

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Figure 1. Figure 1.

Arachidonic acid (AA) metabolism. AA can be converted into biologically active compounds by metabolism by cyclooxygenases, lipoxygenases, or cytochrome P450s.
Figure 2. Figure 2.

Cyclooxygenase (COX) metabolism of arachidonic acid. Both COX‐1 and COX‐2 convert AA to PGH2, which is then acted upon by specific synthases to produce thromboxane A2 or specific prostaglandins (PGs). Prostanoids are converted to inactive metabolites by 15 keto‐PG dehydrogenases.
Figure 3. Figure 3.

Localization of immunoreactive COX‐1 and COX‐2 in the adult mammalian nephron. Immunoreactive COX‐1 is predominantly localized to the afferent arteriole, glomerular mesangial cells, and parietal epithelial cells and the cortical collecting duct. COX‐2 has been localized to afferent arteriole, podocytes, mesangial cells, macula densa, and medullary interstitial cells.
Figure 4. Figure 4.

COX‐2 expression is regulated in renal cortex in rats. Under basal conditions, sparse immunoreactive COX‐2 is localized to the macula densa and surrounding cortical thick ascending limb. In conditions associated with increased renin expression (e.g., low salt), macula densa COX‐2 expression increases markedly.
Figure 5. Figure 5.

Proposed intrarenal roles for vasodilatory prostaglandins (PGs) to regulate renal function and blood pressure control. Alterations in macula densa NaCl reabsorption can lead to increased production of PGs. PGs released from the macula densa, as well as the afferent arteriole, modulate renin expression in juxtaglomerular cells and can also vasodilate the afferent arteriole.
Figure 6. Figure 6.

Proposed role of prostaglandins (PGs) as a modulator of the renin‐angiotensin system. PGs derived from macula densa as well as afferent arteriole can mediate renin production and release, which then mediates production of angiotensin II and aldosterone.
Figure 7. Figure 7.

Differential localization of COX‐1 and COX‐2 in the renal medulla of rodents. COX‐1 is predominantly expressed in the collecting duct and is also found in a subset of medullary interstitial cells, while COX‐2 is predominantly localized to a subset of interstitial cells. D: collecting duct; T: thick limb; V: vasa recta.
Figure 8. Figure 8.

Integrated role of PGE2 on regulation of medullary function. PGE2 can both increase medullary blood flow and directly inhibit NaCl reabsorption in mTAL and water reabsorption in collecting duct.
Figure 9. Figure 9.

Topographic map of COX‐2 expression in kidneys from rats from birth (P0) to adult. Magnifications are equivalent at all stages.
Figure 10. Figure 10.

Prostanoids act predominantly through activation of specific 7‐transmembrane G‐protein‐coupled receptors. Receptors on the left of the figure (IP, DP1, EP2, and EP4 receptors) predominantly active Gs, increase cyclic adenosine monophosphate (cAMP) and are vasodilatory. Receptors on the right of the figure (TP, FP, EP1, EP3, and DP2 receptors) activate either Gi or Gq, decrease cAMP and/or increase intracellular calcium and are vasoconstrictive.
Figure 11. Figure 11.

15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH) immunofluorescent staining in kidney cortex from low salt (LS)‐ or high salt (HS)‐treated rats and cyclooxygenase‐2 (COX‐2) knockout mice. (A) In LS‐treated rat kidney, strong COX‐2 signal was found in the macula densa (arrows) and surrounding thick ascending limb epithelial cells (arrow heads). In these COX‐2‐positive cells, no 15‐PGDH was detected (green; arrows and arrow heads). 15‐PGDH signal was evident in macula densa after high salt treatment but was negative in glomeruli (G). (B) Macula densa15‐PGDH was undetectable in control wild‐type mice but was evident after HS treatment. HS treatment did not increase 15‐PGDH expression in glomeruli. In a COX‐2 knockout mouse, 15‐PGDH was evident in both macula densa (arrows) and glomeruli (G).
Figure 12. Figure 12.

Proposed hemodynamic and renal physiologic functions of prostaglandins and thromboxane A2.


Figure 1.

Arachidonic acid (AA) metabolism. AA can be converted into biologically active compounds by metabolism by cyclooxygenases, lipoxygenases, or cytochrome P450s.



Figure 2.

Cyclooxygenase (COX) metabolism of arachidonic acid. Both COX‐1 and COX‐2 convert AA to PGH2, which is then acted upon by specific synthases to produce thromboxane A2 or specific prostaglandins (PGs). Prostanoids are converted to inactive metabolites by 15 keto‐PG dehydrogenases.



Figure 3.

Localization of immunoreactive COX‐1 and COX‐2 in the adult mammalian nephron. Immunoreactive COX‐1 is predominantly localized to the afferent arteriole, glomerular mesangial cells, and parietal epithelial cells and the cortical collecting duct. COX‐2 has been localized to afferent arteriole, podocytes, mesangial cells, macula densa, and medullary interstitial cells.



Figure 4.

COX‐2 expression is regulated in renal cortex in rats. Under basal conditions, sparse immunoreactive COX‐2 is localized to the macula densa and surrounding cortical thick ascending limb. In conditions associated with increased renin expression (e.g., low salt), macula densa COX‐2 expression increases markedly.



Figure 5.

Proposed intrarenal roles for vasodilatory prostaglandins (PGs) to regulate renal function and blood pressure control. Alterations in macula densa NaCl reabsorption can lead to increased production of PGs. PGs released from the macula densa, as well as the afferent arteriole, modulate renin expression in juxtaglomerular cells and can also vasodilate the afferent arteriole.



Figure 6.

Proposed role of prostaglandins (PGs) as a modulator of the renin‐angiotensin system. PGs derived from macula densa as well as afferent arteriole can mediate renin production and release, which then mediates production of angiotensin II and aldosterone.



Figure 7.

Differential localization of COX‐1 and COX‐2 in the renal medulla of rodents. COX‐1 is predominantly expressed in the collecting duct and is also found in a subset of medullary interstitial cells, while COX‐2 is predominantly localized to a subset of interstitial cells. D: collecting duct; T: thick limb; V: vasa recta.



Figure 8.

Integrated role of PGE2 on regulation of medullary function. PGE2 can both increase medullary blood flow and directly inhibit NaCl reabsorption in mTAL and water reabsorption in collecting duct.



Figure 9.

Topographic map of COX‐2 expression in kidneys from rats from birth (P0) to adult. Magnifications are equivalent at all stages.



Figure 10.

Prostanoids act predominantly through activation of specific 7‐transmembrane G‐protein‐coupled receptors. Receptors on the left of the figure (IP, DP1, EP2, and EP4 receptors) predominantly active Gs, increase cyclic adenosine monophosphate (cAMP) and are vasodilatory. Receptors on the right of the figure (TP, FP, EP1, EP3, and DP2 receptors) activate either Gi or Gq, decrease cAMP and/or increase intracellular calcium and are vasoconstrictive.



Figure 11.

15‐Hydroxyprostaglandin dehydrogenase (15‐PGDH) immunofluorescent staining in kidney cortex from low salt (LS)‐ or high salt (HS)‐treated rats and cyclooxygenase‐2 (COX‐2) knockout mice. (A) In LS‐treated rat kidney, strong COX‐2 signal was found in the macula densa (arrows) and surrounding thick ascending limb epithelial cells (arrow heads). In these COX‐2‐positive cells, no 15‐PGDH was detected (green; arrows and arrow heads). 15‐PGDH signal was evident in macula densa after high salt treatment but was negative in glomeruli (G). (B) Macula densa15‐PGDH was undetectable in control wild‐type mice but was evident after HS treatment. HS treatment did not increase 15‐PGDH expression in glomeruli. In a COX‐2 knockout mouse, 15‐PGDH was evident in both macula densa (arrows) and glomeruli (G).



Figure 12.

Proposed hemodynamic and renal physiologic functions of prostaglandins and thromboxane A2.

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Article Title: Cyclooxygenase Metabolites in the Kidney
 

How to Cite

Raymond C. Harris, Ming‐Zhi Zhang. Cyclooxygenase Metabolites in the Kidney. Compr Physiol 2011, 1: 1729-1758. doi: 10.1002/cphy.c100077