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Cyclooxygenase Biology in Renal Function – Literature Review Biología De La Ciclooxigenasa En La Función Renal – Revisión De La Literatura

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Cyclooxygenase Biology in Renal Function – Literature Review Biología De La Ciclooxigenasa En La Función Renal – Revisión De La Literatura Rev. Colomb. Nefrol. 2017;4(1): 27 - 37. http://www.revistanefrologia.org Review article http://doi.org/10.22265/acnef.4.1.263 Cyclooxygenase biology in renal function – literature review Biología de la ciclooxigenasa en la función renal – Revisión de la literatura Marcella Goetz Moro¹, Paula Katherine Vargas Sánchez¹, Ana Caroline Lupepsa², Emeline Maria Baller², Gilson César Nobre Franco³,*. 1Department of Dentistry, Ponta Grossa State University, Brasil 2Department of Pharmaceutical Sciences, Ponta Grossa State University, Brasil 3Department of General Biology, Ponta Grossa State University, Brasil Abstract The cyclooxygenase (COX) exists in two main isoforms, COX-1 and COX-2, which are present in the renal system to ensure its homeosta- sis. However, in different clinical situations, these enzymes can play a physiologic role in maintaining the integrity of this organ, and also be associated with the worsening of tissue injuries/damage. In this sense, an explanation of the true biological function of the isoforms of COX enables a better understanding of the physiology and pathology of the kidney, as well as a better understanding of the consequences of its inhibition by the use of drugs. This review aimed to study the biological role of the COX enzyme in the renal system in different clinical situations. Key words: Kidney, cyclooxygenase 1, cyclooxygenase 2, pathology, anti-Inflammatory agents, biology. http://doi.org/10.22265/acnef.4.1.263 Resumen La ciclooxigenasa existe en dos isoformas principales: COX-1 y COX-2, estas se encuentran presentes en el sistema renal como parte de su homeostasis. Sin embargo, en algunas situaciones clínicas, las dos enzimas pueden desempeñar un papel en el mantenimiento de la integri- dad de este órgano, y en otras pueden estar asociadas a la evolución de daños y lesiones en los tejidos. En este sentido, el conocimiento de la verdadera función biológica de las isoformas de la COX permite una mejor comprensión de la fisiología y patología del riñón, así como una mejor comprensión de las consecuencias de su inhibición por el uso de medicamentos. El objetivo de esta revisión es estudiar la función biológica de la enzima COX en el sistema renal en diferentes situaciones clínicas. Palabras clave: riñón, ciclooxigenasa 1, ciclooxigenasa 2, patología, antiinflamatorios, biología. http://doi.org/10.22265/acnef.4.1.263 Referenciar este artículo: Goetz Moro M, Vargas Sánchez PK, Lupepsa AC, Baller EM, Nobre Franco GC. Cyclooxygenase biology in renal function – literature review. Rev. Colomb. Nefrol. 2017;4(1): 27 - 37. *Corresponding author: Gilson Cesar Nobre Franco. Universidade Estadual de Ponta Grossa – Departamento de Odontologia – Pós Graduação Stricto Sensu em Odontologia. Av. General Carlos Cavalcanti, nº 4748, Campus de Uvaranas, Ponta Grossa, PR, Brazil. ZIP code: 84030-900, e-mail: [email protected] Received: 12-05-16 • Accepted: 12-02-16 • On line: 07-02-17 Goetz Moro M, Vargas Sánchez PK, Lupepsa AC, Baller EM, Nobre Franco GC 27 Rev. Colomb. Nefrol. 2017;4(1): 27 - 37. http://www.revistanefrologia.org Introduction This process is initiated with the archidonic acid, yclooxygenase (COX), the main catalyst present in the lipid bilayer of the cell membrane, enzyme in the prostanoid synthesis, triggering the prostanoid biosynthesis pathway due has two main known isoforms, COX- to the presence of different stimuli11-16. The pathway C 1,2 involves a sequence of three main steps. Initially, 1 and COX-2 . COX-1, which is responsible for physiological functions, is expressed mainly as the arachidonic acid is liberated, by hydrolysis, 3 a constitutive isoform and, in normal conditions through the action of the phospholipase A2 enzyme (PLA ). Once liberated, the second step begins, with and in distinct regions of the kidney, generates 2 prostaglandins that are responsible for vasodilation oxygenation by the prostaglandin G/H synthase, and diminished vascular resistance, ensuring or cyclooxygenase, resulting in the prostaglandin endoperoxide G (PGG ). In sequence, the same adequate blood flow4. On the other hand, COX-2, 2 2 COX enzymes reduce the PGG into prostaglandin initially considered pathological, is highly expressed 2 H (PGH )15-17. The prostaglandin G/H synthase in the presence of damaging stimuli1. However, this 2 2 has the cyclooxygenase and peroxidase catalytic isoform is now also known to appear constitutively sites. The former converts arachidonic acid into in some tissues, like in the kidney, where it is PGG , which is acted upon by the peroxidase responsible for ensuring the tubuloglomerular 2 enzyme and reduced to the unstable intermediate, feedback, contributing to the establish homeostasis5. PGH2, responsible for the formation of different kinds of prostanoids such as prostacyclin (PGI ), In this sense, although the COX functions have 2 prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), been well-studied in normal situations, studies prostaglandin F (PGF ) and thromboxane A have demonstrated that, facing different clinical 2α 2α 2 (TXA2), through its conversion by the tissue- situations, its isoforms may assume different specific isomerases13,18-20. These prostanoids roles. In cases of hypovolemia and hypertension, provoke different actions in the organism through this enzyme can develop the physiological role of specific receptors, which depend on the type of cell maintaining the integrity of the kidney, as well as and tissue involved in the process (Figure 1) 20-22. becoming associated with the aggravation of tissue lesion/damage, as observed in the polycystic kidney There are different isoforms of COX, but the 4, 6-10 disease . most studied are COX-1 and COX-21. COX-1 was initially named physiological or constitutive for Thus, clarifying the true biological functioning being present in the majority of tissues and being of the COX isoforms enables a better comprehen- expressed in an almost steadily fashion13,19, 23. Its sion of the kidney physiology and pathology, as main role consists of maintaining a basal rate of the well as a better understanding of the consequen- biosynthesis of prostanoids in the body, in order to ces of the isoforms’ inhibition by medication. This promote their rapid, short-duration increase. On the review intended to study the biological role of the other hand, COX-2 is hardly found in most tissues, COX enzyme in the renal system in different clini- but its production increases by approximately 20 ti- cal situations. mes in the presence of inflammatory stimuli. For Cyclooxygenase this reason, it has been called the pathological or in- duced enzyme13,19,23,24. However, recent studies have The cyclooxygenase (COX) is the main enzyme demonstrated that it is also found constitutively in that catalyses the prostaglandin synthesis from ara- some tissues, being responsible for the formation of prostanoids that maintain homeostasis in different chidonic acid. This way, it originates different pros- 1, 24-26 tanoids with different functions in the organism1. organs and systems of the body . 28 Cyclooxygenase biology in renal function – literature review Rev. Colomb. Nefrol. 2017;4(1): 27 - 37. http://www.revistanefrologia.org Captions Membrane phospholipids Physical, chemical, inflammatory Phospholipase A or mitogenic stimulus 2 COOH CH3 Arachidonic acid Prostaglandin G/H synthase (COX) PGG2 Peroxidase PGH2 Tissue-specific isomerases TXA PGE2 PGD2 PGF2a PGI2 2 Figure 1. Prostanoid biosynthesis pathway. Source: author Goetz Moro M, Vargas Sánchez PK, Lupepsa AC, Baller EM, Nobre Franco GC 29 Rev. Colomb. Nefrol. 2017;4(1): 27 - 37. http://www.revistanefrologia.org Cyclooxygenase in renal function Like in COX-1, prostaglandins (PGs) also de- Normal Function rive from COX-2, being important physiological modulators of vascular tone and hydric balance in COX-1 is found in the glomeruli, in the medu- the kidneys13, 35. The prominent PGs in renal tissue llary and cortical region of the collecting ducts and are PGE2 and PGI2, where PGE2 is synthesized by in the afferent and efferent arterioles27, ensuring the the tubular epithelium and interstitial cells, expres- maintenance of the kidney’s physiological func- sed in the renal tubules regulating the transport of tions, such as hemodynamic regulation and glo- chloride and sodium in the Henle loop, besides au- 13, 28-30 merular filtration rate (GFR) . This isoform xiliating water transport and blood flow. PGI2 is lo- produces PGE2 and PGD2, which antagonize the va- cated in the renal cortex, controlling the glomerular soconstrictive action of angiotensin II (Ang II), and filtration rate and renin secretion7, 29. inhibit the release of norepinephrine, respectively31. Hypovolemia In this way, these prostanoids promote vasodilation, increasing the perfusion of the organ Hypovolemia is characterized by a decrease in and causing redistribution in the blood flow from the blood volume, being mainly the result of excessive renal cortex to the nephrons in the intramedullary loss of water in the kidney or hemorrhage. As a con- 31 region . Additionally, the PGE2, alongside the sequence, arterial pressure drops, with the possibili- 13, 31 PGF2α, possess the diuretic and natriuretic effects ty of hypovolemic shock and death . and the PGE2, like the PGI2, antagonize the action of vasopressin31. In a state of hypovolemia with consequent depletion of sodium levels, there is an increase Although COX-2 has been initially considered of COX-2 in the cortical region, and a decrease pathological, is also found constitutively in the of
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