- Role of prostaglandin E2 receptor 4 in the modulation of apoptosis and mitophagy during ischemia/reperfusion injury in the kidney
- Related Articles
- Prostaglandins – Reproduction, Inflammation & Other Conditions
- Prostaglandins and Reproduction
- Prostaglandins and Inflammation
- Prostaglandins and Other Conditions
- The Kinds of Fats
- Cyclooxygenase Deficiency: Practice Essentials, Pathophysiology, Precursors
- Prostaglandins | You and Your Hormones from the Society for Endocrinology
- What are prostaglandins?
- How are prostaglandins controlled?
- What happens if my levels of prostaglandins are too high?
- What happens if my levels of prostaglandins are too low?
Role of prostaglandin E2 receptor 4 in the modulation of apoptosis and mitophagy during ischemia/reperfusion injury in the kidney
- View Affiliations Affiliations: Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Traditional Chinese Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Published online on: August 8, 2019 https://doi.org/10.3892/mmr.2019.10576
- Pages: 3337-3346
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The mechanisms by which prostaglandin E2 receptor 4 (EP4) protects against renal ischemia‑reperfusion (I/R) injury (IRI) remain to be fully elucidated.
In the present study, the protective effects of EP4 signaling on renal mitochondria and against renal IRI, as well as the underlying mechanisms, were investigated. A rat model of renal IRI was established.
The right kidney was separated without damaging the artery clip, and the renal blood perfusion was then restored after 60 min. One group of animals was treated with EP4 agonists prior to I/R.
The mitochondrial mass, the copy number of mitochondrial (mt)DNA, adenosine triphosphate (ATP) production and mitochondrial autophagy were analyzed. It was identified that renal IRI reduced the mitochondrial mass, decreased the mtDNA copy number and inhibited ATP production.
The loss of renal mitochondria was attributed to the excessive mitochondrial autophagy induced by renal IRI. Pre‑treatment with EP4 agonist inhibited excessive mitochondrial autophagy, the loss of mitochondria and maintained and the energy imbalance within the cells. It was indicated that renal IRI causes excessive mitochondrial autophagy, which is one of the important causes of renal dysfunction.
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Prostaglandins – Reproduction, Inflammation & Other Conditions
These natural chemicals in the body play a role in reproduction, as well as in promoting and resolving inflammation.
Prostaglandins are natural chemicals in the body with hormone- qualities.
First discovered in semen, prostaglandins were later found in cells throughout the body, as well as in women's menstrual fluid.
Prostaglandins affect reproductive processes and are also thought to play a major role in promoting and resolving inflammation in the body.
While most hormones are released by a gland and then carried throughout the body in the bloodstream, prostaglandins are not. Rather, they're produced at the area of the body where they're needed.
Prostaglandins and Reproduction
Although more research is needed to fully understand the role of prostaglandins in reproduction, it's known that they're present in the body throughout a woman's menstrual cycle.
During your period, prostaglandins trigger muscles in your uterus to contract. These contractions help expel the uterus lining.
Higher levels of prostaglandins can cause more severe menstrual cramps, and severe contractions may constrict the blood vessels around the uterus.
When pregnant women go into labor, prostaglandins help cause the cervix to dilate and contractions to occur.
Your doctor may use prostaglandins to induce labor if it's decided that you should give birth before labor naturally occurs.
Dinoprostone (Prepidil gel or Cervidil) inserts are used for this purpose.
The following risks and side effects are possible with induced labor:
- Uterine hyperstimulation, a serious complication that can cause injury and bleeding
Prostaglandins are also used to:
- Control excessive bleeding after giving birth
- Manage patent ductus arteriosus, a condition in which the ductus arteriosus (a blood vessel) doesn't close in an infant after birth
- Terminate a pregnancy
Prostaglandins may also play a role in erections in men. Because of this role, they have been synthesized and used in injections to help men with erectile dysfunction (ED) obtain an erection.
ED occurs when a man consistently can't get an erection or maintain one long enough to engage in sexual intercourse.
Prostaglandins and Inflammation
When part of your body is inflamed, it means that your immune system is responding to infection or injury.
Inflammation is a way for your body to try to heal damaged areas, but it can also get control and cause damage over time.
Inflammation has been shown to play a role in arthritis, lupus, cancer, and neurodegenerative and cardiovascular diseases.
Prostaglandins play a key role in inflammation by contributing to the development of redness, swelling, heat, and pain.
Excess production of prostaglandins due to inflammation may lead to:
- Heavy menstrual bleeding
- Painful menstrual cramps
While researchers understand prostaglandins well when it comes to promoting inflammation, they don’t understand how these chemicals help resolve inflammation.
Prostaglandins and Other Conditions
If your body doesn't produce enough prostaglandins, your doctor may consider giving you prostaglandins to treat the following conditions:
- Stomach ulcers
- Congenital heart disease in newborn babies
The Kinds of Fats
Prostaglandins are short-range hormones that are used in a great many different body tissues to regulate a great many things. Among these is inflammation.
Inflammation can be good, as in the swelling that follows an injury, which is a good “natural splint” that helps immobilize the injured region.
Inflammation can also be bad, when our response to environmental conditions leads to chronic inflammatory diseases asthma, or to more serious inflammatory diseases rheumatoid arthritis.
What are these hormones, and how are they made?
The diagram below illustrates the basic process, beginning with a phospholipid. Normally, phosopholipids are in the cell membrane. Certain enzymes can cut the phospholipid, however, and release free fatty acids.
One such fatty acid is used to build the family of prostaglandins and related inflammatory signaling molecules (such as leukotrienes). The “normal” family of prostaglandins is produced from an ω-6 fatty acid.
These are typically reffered to as the “series 2” prostaglandins, because in their end form, they contain two double bonds.
Supplementation of the diet with adequate amounts of ω-3 fatty acids makes it possible for cells to use these fatty acids instead, and produce a set of these hormones called the “3-series.” These have a third double bond (derived from the ω-3 double bond of the original fatty acid, highlighted above in yellow.
The product of the set of reactions illustrated above is Prostaglandin H2. It serves as the starting material for building the actual signaling molecules. The followin illustration (from Wikipedia) shows the diversity of possible fates for PGH2:
Needless to say, there's “a whole bunch” of different molecules here. Each does its own thing, telling different types of cells in different parts of the body to do different types of things.
Most of the information available — and most of the interesting findings — concern PGE2, in the middle right of the above illustration.
The interesting comparison is with PGE3, the analogous molecule produced from the ω-3 fatty acid, instead of the ω-6 fatty acid.
PGE2 is an inflammatory mediator. When it is produced, it triggers inflammation.
It is commonly produced in response to wounding, but can also be produced in a chronic fashion — not produced as rapidly, but over a very long time.
As with the production of the other prostaglandins, its production is blocked by aspirin and other similar non-steroidal anti-inflammatories. This is how they function.
PGE3 behaves differently. Cells that produce it seem not to respond to their own signaling, the way that PGE2-producing cells do. Other cells seem to respond to PGE3 more slowly, and less dramatically. As a result, a diet rich in ω-3 fatty acids causes the production of this form of the signaling molecule, which tends to lessen the degree of inflammation.
Acute inflammation due to injury still produces enough PGE2 to perform the necessary tasks of recovery, but the PGE3 seems a good candidate for lessening chronic inflammation. If we think of our bodies as responding systems, we might call them “twitchy” when they rely solely, or primarily on PGE2. Adding PGE3 removes the “twitchiness.”
The ratio of ω-3 to ω-6 fatty acids
Much is said in the popular literature, and in dietary supplement and natural foods websites, about the ratio of the important unsaturated fatty acids.
It is estimated that the “natural” diet (before food-processing and possibly pre-agriculture) gave us far more ω-3's that we now consume.
With a similar, or higher quantity of ω-6's in our diets (higher due to food processing, and the replacement of grass with grain for animal feed), the ratio of 3's to 6's has gone way down.
The medical literature has not reported that the ratio is particularly important. It may prove to be after the studies have been done, but so far, the evidence is lacking. More significant is the total quantity of ω-3 fatty acids.
This makes sense: the ω-3's are a minority of the total fatty acids in any event, so increasing our intake of these will have a bigger impact on the overall ratio of 3's to 6's than will decreasing the amount of ω-6's. It's pretty easy, for example, to increase a low number (say, 2) by 100% (to another low number, 4).
It's much harder to decrease a large number (say, 200) by the same factor (down to 100).
If one intentionally chooses to follow a dieatary strategy that maximizes ω-3 fatty acids, it is ly that that total quantity of ω-6's will decrease on its own without special attention.
Grass-fed beef is preferable to feedlot beef for a number of reasons, the fatty acid content being one of the less pressing. It also makes sense to eat a wider variety of fruits and vegetables, rather than eat potatoes as the primary or only vegetable in the diet.
The colored compounds (and many of the non-colored ones) in fruits, vegetables, and leafy greens act as antioxidants, and have their own health benefits. Eating whole foods, prepared at home by yourself, rather than eating processed convenience foods, has further benefits.
Good meals is one; so is the benefit of getting to know your family again, as you sit around the table and enjoy dinner.
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Cyclooxygenase Deficiency: Practice Essentials, Pathophysiology, Precursors
As previously noted, COX metabolizes arachidonic acid (5,8,11,14-eicosatetraenoic acid) into PGH2 intermediates.
Subsequently, PGH2 is converted into biologically active products via cell-specific enzymatic reactions.
The products include not only classic prostaglandins (ie, prostaglandin D2 [PGD2], PGE2, prostaglandin F2-alpha [PGF2-alpha]), but also prostacyclin (PGI2) and thromboxane A2 (TXA2). 
Besides these dienoic products, COX metabolizes analogous fatty acids into monoenoic and trienoic prostaglandins and thromboxanes as a consequence of the number of precursor double bonds. Collectively, their diverse properties are implicated in several physiologic processes as receptor-dependent mediators and as intracellular secondary messengers.
However, the potencies of different monoenoic, dienoic, and trienoic prostaglandins and thromboxanes vary with respect to each family. Studies emphasize that the products are particularly influential in local biologic environments, because of their rapid conversion to inactive metabolites.
Hence, precursor availability and enzyme kinetics play a key role in the regulation of individual responses.
TXA2, the predominate product of COX in platelets and macrophages, is converted from PGH2 by thromboxane synthase. The structural characteristics include a 6-membered ring containing an ether, as depicted in the image below.
The functional characteristics include platelet aggregation, vascular smooth muscle constriction, and bronchial smooth muscle constriction with a corresponding 30-second tissue half-life. Furthermore, TXA2 has a different affinity for each eicosanoid-specific receptor because of distinct receptor ligands.
As a result, the physiologic responses via TXA2 are tailored to the situation and are less haphazard when stimulated. 
Thromboxane A2 (TXA2).
PGI2, the predominate product of COX in microvascular endothelium, is converted from PGH2 by PGI2 synthase. The structural characteristics include not only a 5-member ring, similar to all prostaglandins, but also an enzyme-specific arrangement of respective hydroxyl and carbonyl groups, as shown below.
The functional characteristics include inhibition of platelet aggregation, inhibition of platelet and neutrophil adhesion, dilation of bronchial and vascular smooth muscle, and modulation of cholesterol efflux from arterial walls with a corresponding 3-minute tissue half-life.
Furthermore, the biosynthesis of PGI2 is enhanced in the face of thrombogenesis and vasoconstriction to balance the physiologic milieu, not un several well-known stimulation/inhibition processes. 
PGD2, the predominate product of COX in mast cells, is converted from PGH2 by endoperoxide-D isomerase. Again, the structural characteristics are similar to those of all other prostaglandins.
The functional characteristics include symptoms associated with histamine release (eg, hypotension) and poorly defined roles associated with immunologic processes.
However, the formation of 9-alpha,11-beta-prostaglandin F (PGF) metabolites by preferential conversion of PGD2 results in the inhibition of platelet aggregation and the contraction of vascular smooth muscle tissue. This might explain the occasional hypertensive patient observed with systemic mastocytosis.
PGE2 is a significant product of COX in the gastric mucosa, renal medulla, and microvascular endothelium, as well as in some tumors. [13, 14] This biologically active product is converted from PGH2 by endoperoxide-E isomerase. Although the products are structurally related, each functional temperament is curiously diverse. (See the image below.)
Prostaglandin E2 (PGE2).
In the gastric mucosa, PGE2 preserves integrity by influencing mucus and bicarbonate secretion.  It also maintains mucosal blood flow and participates in cellular repair. In the renal medulla, PGE2 enhances vasodilatation and inhibits tubular sodium absorption.  Hence, a deficiency of PGE2, as observed in essential hypertension, results in unopposed vasoconstriction.
Further attributes include stimulation of local osteoclasts, relaxation of bronchial smooth muscle tissue, contraction of uterine smooth muscle tissue, and modulation of presynaptic adrenergic neuron receptors. Despite vague interpretation, PGE2 is hypothesized to also be a key participant in local inflammatory responses. [16, 17]
Prostaglandins | You and Your Hormones from the Society for Endocrinology
Prostaglandin D2; prostaglandin E2; prostaglandin F2; prostaglandin I2 (which is also known as prostacyclin); a closely related lipid called thromboxane
What are prostaglandins?
Mechanism of action of the drug aspirin. Aspirin works by stopping prostaglandin being made: aspirin molecules (blue hexagons) enter the cell and chemically modify the cyclooxygenase enzyme (purple) to prevent prostaglandin being made.
Un most hormones, which are produced by glands and transported in the bloodstream to act on distant areas of the body, the prostaglandins are produced at the site where they are needed. Prostaglandins are produced in nearly all cells and are part of the body’s way of dealing with injury and illness.
Prostaglandins act as signals to control several different processes depending on the part of the body in which they are made. Prostaglandins are made at sites of tissue damage or infection, where they cause inflammation, pain and fever as part of the healing process.
When a blood vessel is injured, a prostaglandin called thromboxane stimulates the formation of a blood clot to try to heal the damage; it also causes the muscle in the blood vessel wall to contract (causing the blood vessel to narrow) to try to prevent blood loss.
Another prostaglandin called prostacyclin has the opposite effect to thromboxane, reducing blood clotting and removing any clots that are no longer needed; it also causes the muscle in the blood vessel wall to relax, so that the vessel dilates.
The opposing effects that thromboxane and prostacyclin have on the width of blood vessels can control the amount of blood flow and regulate response to injury and inflammation.
Prostaglandins are also involved in regulating the contraction and relaxation of the muscles in the gut and the airways.
Prostaglandins are known to regulate the female reproductive system, and are involved in the control of ovulation, the menstrual cycle and the induction of labour. Indeed, manufactured forms of prostaglandins – most commonly prostaglandin E2 – can be used to induce (kick-start) labour.
How are prostaglandins controlled?
The chemical reaction that makes the prostaglandins involves several steps; the first step is carried out by an enzyme called cyclooxygenase. There are two main types of this enzyme: cyclooxygenase-1 and cyclooxygenase-2.
When the body is functioning normally, baseline levels of prostaglandins are produced by the action of cyclooxygenase-1.
When the body is injured (or inflammation occurs in any area of the body), cyclooxygenase-2 is activated and produces extra prostaglandins, which help the body to respond to the injury.
Prostaglandins carry out their actions by acting on specific receptors; at least eight different prostaglandin receptors have been discovered. The presence of these receptors in different organs throughout the body allows the different actions of each prostaglandin to be carried out, depending on which receptor they interact with.
Prostaglandins are very short-lived and are broken down quickly by the body. They only carry out their actions in the immediate vicinity of where they are produced; this helps to regulate and limit their actions.
What happens if my levels of prostaglandins are too high?
High levels of prostaglandins are produced in response to injury or infection and cause inflammation, which is associated with the symptoms of redness, swelling, pain and fever. This is an important part of the body’s normal healing process.
However, this natural response can sometimes lead to excess and chronic production of prostaglandins, which may contribute to several diseases by causing unwanted inflammation. This means that drugs, which specifically block cyclooxygenase-2, can be used to treat conditions such as arthritis, heavy menstrual bleeding and painful menstrual cramps.
There is also evidence to suggest that these drugs may have a beneficial effect when treating certain types of cancer, including colon and breast cancer, however research in this area is still ongoing. New discoveries are being made about cyclooxygenases which suggest that cyclooxygenase-2 is not just responsible for disease but has other functions.
Anti-inflammatory drugs, such as aspirin and ibuprofen, work by blocking the action of the cyclooxygenase enzymes and so reduce prostaglandin levels. This is how these drugs work to relieve the symptoms of inflammation. Aspirin also blocks the production of thromboxane and so can be used to prevent unwanted blood clotting in patients with heart disease.
What happens if my levels of prostaglandins are too low?
Manufactured prostaglandins can be used to increase prostaglandin levels in the body under certain circumstances.
For example, administration of prostaglandins can induce labour at the end of pregnancy or abortion in the case of an unwanted pregnancy.
They can also be used to treat stomach ulcers, glaucoma and congenital-heart-disease'>congenital heart disease in newborn babies. Further advances in understanding how prostaglandins work may lead to newer treatments for a number of conditions.
Last reviewed: Oct 2019