Prostaglandins as potential targets for the treatment of polycystic kidney disease (2023)


Polycystic kidney disease (PKD) comprises a group of disorders characterized by the proliferation of fluid-filled kidney cysts. These cysts cause progressive damage to the normal renal parenchyma, eventually leading to progressive renal failure. The most common form of PKD and the most common monogenetic cause of kidney disease is autosomal dominant PKD (ADPKD), formerly referred to as adult-onset PKD because kidney failure usually occurs later in life. Another form of the disease that is much less common but more severe is autosomal recessive PKD, which affects children. Other less common forms of cystic kidney disease include a genetically diverse group of medullary cystic diseases caused by numerous mutations in genes associated with nephropathy, other medullary cystic kidney diseases, Joubert syndrome, Meckel syndrome, Bardet-Biedel syndrome, and orofacial digital syndrome. 1]. ], [2], [3].

ADPKD occurs worldwide in all races, with a prevalence of 1 in 1,000 estimated by population sequencing [4] and 1 in 2,000 when estimated from epidemiological data [5], [6], [7]. In Canada, 7.4% of patients receiving renal replacement therapy have ADPKD [8]. One review reported that men with ADPKD develop kidney failure three to five years earlier than women, but women with more than three pregnancies are at increased risk of end-stage renal disease [9]. A recent re-analysis of the HALT-PKD studies was unable to demonstrate gender-specific differences in disease course [10]. However, the actual effect of gender is still unknown. Kidney failure occurs in about 50% of patients, usually between the ages of 50 and 70. Treatment of patients with CKD includes controlling blood pressure, maintaining fluid intake, managing pain, kidney stones, urinary tract infections, and elevated lipids, and promoting moderate intakes of sodium, protein, phosphorus, and calories [ 11,12]. , but these do not target PKD itself. Pain and hematuria are the most common symptoms in ADPKD [13]. Other complications include liver cysts [14,15], cardiac abnormalities [14], [15], [16], kidney stones [17], diverticulitis [18], and intracranial aneurysms [19,20].

The proteins that are mutated (or modified [21]) in ADPKD, namely polycystin 1 (ADPKD1) and 2 (ADPKD2), are involved in the development of the kidney as well as the liver, heart, brain and other tissues, but the results are previously due mainly to the kidneys. Defects in any of these proteins result in loss of proper renal cell orientation and secretion, increased epithelial cell proliferation, cyst formation, and fluid secretion in the expanding cysts. These events ultimately cause remodeling of the extracellular matrix, fibrosis and inflammation leading to renal failure [2]. Numerous fluid-filled cysts develop in the kidneys of PKD patients, which continue to grow and expand throughout life until they damage the surrounding tissue and interfere with normal kidney function.

A key feature of PKD is increased epithelial cell proliferation, which is required for cyst enlargement. The first studies showed that c-was GProto-oncogene was elevated in cystic kidneys [22,23] and several PKD models are characterized by reduced survivin expression, cell ploidy and asymmetric cell division, resulting in loss of planar cell polarity associated with increased cell proliferation in cystic kidneys. kidneys [24]. Cyclic adenosine monophosphate (cAMP)-stimulated increased activity of mitogen-activated protein kinase (MAP) appears to be an important signaling pathway in PKD. cAMP normally inhibits cell proliferation, but in cystic kidneys with low intracellular calcium levels it stimulates signaling pathways that promote proliferation [25], [26], [27]. Indeed, renal cAMP is increased in several models of PKD [28], [29], [30], [31], [32], [33] and prostaglandin (PG)E2cAMP-mediated production stimulates cell proliferation and cyst formation in primary cultured ADPKD cells [25,34,35]. cAMP activates protein kinase A (PKA), which among others stimulates B-Raf and the MAP kinase cascade in bladder epithelial cells, leading to increased cell proliferation [26].

Another hallmark of PKD is increased fluid secretion, which is also associated with elevated cAMP levels, as cAMP stimulation stimulates fluid secretion and tubule dilation in cystic cells and organ cultures [36], [37], [38]. ], [39] and in intact cysts [40]. A number of transporters appear to be altered in PKD, including the cystic fibrosis transmembrane conductance regulator (CFTR) [41]. Inhibition of CFTR inhibits chloride secretion in ADPKD cells and tubular dilation in vitro [38,42] and CFTR inhibitors slow disease progression in vivo [43]. CFTR is also regulated by cAMP through PKA-dependent phosphorylation of its regulatory domain [44,45]. In addition, the calcium-activated potassium channel KCa3.1 is involved in cyst fluid secretion, and this transporter is also activated by cAMP [ 46 ].

Ultimately, increased cell proliferation and development of fluid-filled cysts leads to localized tissue damage, leading to increased repair and fibrosis characterized by increased collagens, metalloproteinases, integrins, and β-catenins [2,47]. This is accompanied by increased secretion of inflammatory mediators such as monocyte chemoattractant protein-1, macrophage migration inhibitory factor, renal injury molecule-1, tumor necrosis factor α and osteopontin as well as increased inflammatory cell infiltration [48], [49], [50]. ], [51] , [52], [53]. Although PKD is not considered an inflammatory disease, this increased inflammatory response can also promote cyst development, which in turn further accelerates disease progression, all of these events eventually leading to renal failure [50, [54] , [55] , [56] ]. ].

As previously mentioned, cAMP is an important mediator of PKD pathology, and interventions targeting the cAMP pathway are being developed to treat this disease [ 57 ]. Increased cAMP levels following activation of G protein-coupled receptors with ligands lead to PKA activation by causing dissociation of regulatory subunits from catalytic subunits. In cells containing B-Raf, increased PKA activity can stimulate the MAP kinase cascade, resulting in extracellular signal-regulated kinase (ERK) phosphorylation [58]. In turn, ERK and other MAP kinases can activate transcription factors that bind to cAMP-responsive elements, such as B. cAMP-responsive element binding protein, cAMP-responsive element modulator protein, cAMP-inducible early repressor, and activator transcription factor-1, which regulate a multitude of genes involved in cellular processes such as proliferation and growth [59] . Increased cAMP-stimulated MAP kinase activity appears to be an important signaling pathway in PKD, as cAMP normally inhibits cell proliferation, but in cystic kidneys with low intracellular calcium levels it stimulates this pathway [ [25] , [26] , [27], 60], 61].

The vasopressin (AVP) receptor antagonist tolvaptan reduces cAMP levels in the kidney and is the only drug approved for the treatment of ADPKD. AVP binds to V2Receptors along the peripheral nephron and collecting duct, resulting in increased ion and fluid transport, renal reabsorption of electrolytes, and increased urine concentration [62]. An assembly defect has long been documented in various forms of PKD [63], [64], [65], [66], [67], which is due at least in part to defective AVP signaling [68]. Binding AVP to V2The receptors activate adenylyl cyclase, leading to an increase in cAMP. Several studies have shown that AVP antagonists reduce disease in multiple PKD models and cyst growth of human ADPKD cells in vitro by reducing adenylyl cyclase activity and cAMP formation [31, [69], [70], [71], [72]. ]. Efficacy and safety of tolvaptan in the treatment of autosomal dominant polycystic kidney disease and its sequelae (TEMPO) [73,74] and replicative evidence of preserved renal function: Tolvaptan Safety and Efficacy Study (7REP) [7REP] showed the ability of Tolvaptan to slow ADPKD in a wide range of disease states, confirming previous preclinical studies [31,69,70,76,77]. Tolvaptan treatment did not cure the disease but slowed the decline in eGFR by 0.4-1.7 mL/min/1.73 m2per year in human trials. This represents an approximately 25% lower reduction in early disease stages [73,74] and an approximately 35% lower reduction in late disease stages [75]. These and other studies [12,78,79] led to the approval of tolvaptan for the treatment of ADPKD in Europe and several countries, including Canada, the United States, and Australia.

Somatostatin analogs also decrease cAMP by stimulating other G protein-coupled receptors that reduce adenylyl cyclase activity and slow kidney enlargement in human ADPKD patients and in rodent models of PKD [80] , [81] , [82] . However, this treatment results in side effects in 80-90% of patients, with 10% of patients in the treatment group suffering from cholelithiasis or acute cholecystitis. Further support for a role of cAMP in PKD is that adenylyl cyclase 5 iPkd2WS25/−Mice have reduced renal cAMP and disease progression [83] and that increasing cAMP levels through phosphodiesterase reduction in ADPKD models accelerates disease progression [84]. However, inhibition of adenylyl cyclases is associated with attenuation of neurological, cardiac and pain responses [85], [86], [87].

It has also been suggested that ADPKD patients reduce exposure to agents (eg, caffeine, forskolin) that increase cAMP levels [88,89]. Another way to reduce AVP levels is to increase water intake, which has been shown to be effective in reducing kidney cAMP levels and slowing disease in the PCK rat model of autosomal recessive PKD [90]. Alterations in signaling proteins downstream of cAMP have also been detected in several models of PKD [90,91]. In addition, cAMP agonists such as forskolin stimulate cell proliferation and fluid secretion in ADPKD cells, and inhibitors (eg, sorafenib) of cAMP-dependent activation of B-Raf and ERK signaling reduce cell proliferation and growth of cysts in vitro in ADPKD cells [25, 27 , [92], [93], [94]]. Recently, the role of altered mitochondrial biogenesis has been investigated [95,96], with these defects thought to lead to increased glycolysis and cell proliferation in PKD [97]. In the context of PKD, decreased calcium and increased cAMP reduce the expression of peroxisome proliferator-activated receptor γ-coactivator 1α, a master regulator of mitochondrial biogenesis, placing cAMP upstream of the mitochondrial and metabolic defects in PKD [96].

Fluid secretion is another important component of PKD that is also associated with increased cAMP levels, as cAMP stimulation stimulates fluid secretion and tubular dilation in cystic cells and organ cultures [36], [37], [38], [ 39]. and in intact cysts [40]. Several cAMP-regulated transporters appear to be altered in PKD, including CFTR [38, [41], [42], [43]] and the calcium-activated potassium channel KCa3.1 [46]. Inhibition of CFTR inhibits chloride secretion in ADPKD cells and tubular dilation in vitro [38,42] and CFTR inhibitors slow disease progression in vivo [43].

section excerpt

Evidence of increased PG levels in PKD

Thus, there is overwhelming data showing reduction of cAMP levels or signaling pathways activated by cAMP as an effective means of reducing important features of PKD: increased cell proliferation, cyst development, and fluid secretion. In this regard, PG is a class of lipid mediators that are altered in PKD and mediate its action by altering cAMP levels. PG-mediated cAMP production stimulates cell proliferation and cyst formation in primary cultured ADPKD cells [25,34,35]. Although PG is usually low

(Video) Polycystic kidney disease: Mayo Clinic Radio

Details on the specific role of the PGI2and Civil Code2in PKD and effects on cAMP

The benefits of targeting specific PG receptors in PKD are the observation that not all PGs were increased during the course of the disease and not all increases were reduced by celecoxib. The two PGs most common in normal kidneys, which are overduplicated in disease, were PGD2and Civil Code2(as measured by the stable metabolite 6-keto-PGF1a). These PGs were reduced by 20–30% with celecoxib treatment in diseased kidneys without any effect in normal kidneys. In contrast, PGE2

Summary and future directions

We have shown in several PKD models that PG levels are elevated in diseased kidneys and that celecoxib treatment reduces PGD in an ADPKD model2and Civil Code2and slows the progression of the disease. PG mediates its action through a key mechanism in the development and progression of PCD, i.e., increased cAMP, which is associated with increased cell proliferation, cyst development, and fluid secretion. Therefore, treatment with receptor agonists/antagonists specific to these PGs may help us understand more

Declaration of Competing Interests


Featured Articles (6)

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    Tramadol, a weak μ-opioid receptor (MOR) agonist with inhibitory effects on serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake, is a potent analgesic for chronic pain. Osteoprotegerin produced by osteoblasts is essential for bone remodeling to suppress osteoclastic bone resorption. We have previously reported that prostaglandin D2(PID2) induces osteoprotegerin synthesis, with p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase and stress-activated protein kinase/c-junN-terminal kinase (SAPK/JNK) is involved in osteoblast-like MC3T3-E1 cells. Here we examined the mechanism underlying the effect of tramadol on PGD2-induced osteoprotegerin synthesis in these cells. Tramadol improved PGD2-induced release and expression of osteoprotegerin mRNA. Naloxone, an MOR antagonist, reduced the potentiation of PGD by tramadol2- The release of osteoprotegerin is stimulated. Not the selective norepinephrine reuptake inhibitor revoxetine, but the selective serotonin reuptake inhibitors fluvoxamine and sertraline upregulate PGD2-caused osteoprotegerin release which was further enhanced by morphine. Enhanced PID with tramadol2- stimulation of phosphorylation of p38 MAP kinase and SAPK/JNK but not p44/p42 MAP kinase. Both SB203580 and SP600125 suppressed the PGD-enhancing effects of tramadol2- The release of osteoprotegerin is stimulated. Tramadol improved PGE2-induced release of osteoprotegerin and PGD2. These results suggest that tramadol increases PGD2-induced osteoprotegerin synthesis before p38 MAP kinase and SAPK/JNK in the involvement of MOR and 5-HT transporters in osteoblasts.

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    The effect of polyunsaturated fatty acid deficiency on the allergic response in mice immunized with ovalbumin

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    Polyunsaturated fatty acids (PUFAs) are present in biological membranes and affect membrane fluidity and the immune response. PUFAs such as 18:2n-6 and 18:3n-3 cannot be synthesizedOne more timein mammals and are therefore called essential fatty acids (EFAs). In addition, PUFAs can be converted in the body to very long-chain PUFAs (VLC-PUFAs) such as arachidonic acid and docosahexaenoic acid. Although allergen avoidance is an effective strategy for patients with food allergies, dietary exclusion of multiple allergens has been reported to lead to deficiencies in essential nutrients such as PUFAs. In this study, we investigated whether an EFA-deficient (EFAD) diet affects allergic symptoms in mice immunized with ovalbumin (OVA). Unexpectedly, no impairment of the immune response was observed after OVA sensitization in mice fed the EFAD diet, and no differences in serum PUFA levels were observed between OVA-immunized and non-immunized mice fed the EFAD diet. However, small intestinal VLC-PUFA levels increased after OVA sensitization and did not decrease upon EFAD diet administration, indicating that small intestinal VLC-PUFA levels were largely preserved in the mouse models of food allergy. Further studies are needed to elucidate the mechanisms by which small intestinal VLC PUFAs are preserved in mouse models of food allergy.

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    Safety and efficacy of Evacetrapib in patients with poorly controlled hypercholesterolemia and high cardiovascular risk. A meta-analysis of randomized placebo-controlled trials

    Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 168, 2021, Article 102282

    Low-density lipoprotein cholesterol (LDL-C) is causally linked to cardiovascular disease. Cholesterol ester transfer protein inhibition with evacetrapib may provide an additional treatment option for patients unable to achieve their LDL-C goals on statins or who are intolerant to statins. Our objective was to evaluate the safety and efficacy of evacetrapib in patients with poorly controlled hypercholesterolemia and high cardiovascular risk.

    An online literature search of PubMed, Scopus and Science Direct was performed from inception to 2019 and updated from January 2019 to March 2021. We included only RCTs. Data were pooled as the mean difference in a random effects model using the Mantel–Haenzel (M–H) method. We used Open Meta [Analyst] software (at the Center for Evidence-Based Medicine, University of Oxford, UK).

    Five Studies (N=12,937 patients) reported in five articles were included in this meta-analysis. The pooled overall estimate showed that LDL-C was significantly lower in the evacetrapib group than in the placebo group (MD -34.07 mg/dL, 95% CI [-40.66, -27.49] ,small<0.0001). The pooled estimate showed that apo-B was significantly lower in the evacetrapib 130 mg group than in the placebo group (MD -22.64 mg/dL, 95% CI [-30.70, -14.58 ] ).small<0.0001). HDL-C was significantly higher in the evacetrapib group compared to the placebo group (MD 93.31 mg/dL, 95% CI [56.07; 130.56]).small<0.0001).

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    Recent data from five RCTs (12,539 participants) suggest that evacetrapib has favorable effects in patients with poorly controlled hypercholesterolemia and high cardiovascular risk. Evacetrapib could significantly increase HDL and apo-A1 levels and decrease LDL-cholesterol and apo-B levels, with an acceptable safety profile.

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    To monitor the effect on total liver volume (TLV) on and off treatment in selected symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PLD) receiving octreotide extended-release tablets ( OctLAR) up to 4 years took years.

    Twenty-eight of 42 participants in a prospective two-year clinical study of OctLAR (40 mg monthly) consisting of double-blind, randomized (Year 1) and open-label (Year 2) treatment periods were re-enrolled in a two-year open-label extension (OLE) study. after a mean of 8.3 months off OctLAR (initial study: July 1, 2007 to June 30, 2013). Participants underwent MRI at baseline, at years 1 and 2, at re-enrollment, and at study discontinuation. Primary endpoint: change in TLV. Secondary endpoints: changes in total kidney volume, glomerular filtration rate, quality of life (QoL), safety, vital signs and laboratory parameters.

    25 participants (59.5%) completed the OLE. Off-treatment, TLVs increased by a mean ±SD of 3.4% ±8.2% per year. After restarting treatment, TLVs decreased by a mean ± SD of -4.7% ± 6.1% per year. Despite regrowth after treatment, overall reductions were observed with a median (interquartile range) TLV of 4047 mL (3107-7402 mL) at baseline and 3477 (2653-7131 mL) at study end (-13.2%).Pi<.001) and with improved health-related quality of life. Total renal volume increased and glomerular filtration rate decreased from 58.2 mL/min to 54.5 mL/min (n=16) in treated ADPKD patients from baseline to study end.

    Treatment with OctLAR for 4 years in selected patients with symptomatic PLD halted the progression of PLD, relieved symptoms and improved health-related quality of life. The interruption led to organ regrowth.

    Clinicaltrials.govID CARD:NCT00426153.

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    Hereditary cystic kidney disease is one of the most important monogenic causes of kidney disease, causing significant morbidity and mortality in both children and adults. Significant progress has been made in recent decades in identifying and characterizing the genes responsible for these diseases. In this chapter, the genetic aspects, molecular pathogenesis, clinical features and treatment of these diseases are highlighted.

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    Lanreotide reduces liver growth in patients with autosomal dominant polycystic liver and kidney disease

    Gastroenterology, Volume 157, Issue 2, 2019, pp. 481-491.e7

    Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Reliable long-term evidence of the volume-reducing effect of somatostatin analogues is needed. We used data from an open-label, randomized study to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLV) in patients with ADPKD.

    We conducted a 120-week study comparing the protective effects of lanreotide versus standard care in 305 patients with ADPKD (DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with liver cysts detected by MRI and a liver volume ≥ 2000 mL. Of these, 93 patients were divided into a group receiving lanreotide (120 mg subcutaneously every 4 weeks) and 82 into a group receiving standard care (blood pressure control, low-sodium diet, and antihypertensive drugs). The primary endpoint was percentage change in hTLV from baseline to end of treatment (week 120). A secondary endpoint was change in hTLKV.

    At 120 weeks, hTLV decreased by 1.99% (95% confidence interval [CI], -4.21 to 0.24) in the lanreotide group and increased by 3.92% (95% CI, 1.56- 6:28). Compared with the control group, lanreotide reduced the development of hTLV by 5.91% (95% CI, -9.18 to -2.63;Pi< 0.001). hTLV growth was still reduced by 3.87% from baseline 4 months after the last lanreotide injection (95% CI, -7.55 to -0.18;Pi= 0.04). Lanreotide reduced the growth of hTLKV compared with controls by 7.18% (95% CI, -10.25 to -4.12;Pi< 0.001).

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    In this sub-analysis of a randomized study in patients with polycystic liver disease due to ADPKD, lanreotide reduced liver growth and combined liver and kidney volume over 120 weeks. This effect was still present 4 months after the last lanreotide, Number:NCT01616927

© 2020 Elsevier Ltd. All rights reserved.


What do prostaglandins do to the kidneys? ›

Prostaglandins (PGs) regulate vascular tone and salt and water homeostasis in the mammalian kidney and are involved in the mediation and/or modulation of hormonal action.

What are the targets of PKD? ›

Potential therapeutic targets in PKD are ACE, the angiotensin receptor and renin.

Why are ACE inhibitors used for PKD? ›

ACE inhibitors provide excellent blood pressure control and lower urine protein in PKD. Further large-scale studies are required to determine the efficacy of ACE inhibitors on progression of PKD.

What do prostaglandins do to afferent arteriole? ›

Our findings indicate that PGE2 exerts a selective effect on the afferent arteriole, eliciting both vasodilation and vasoconstriction of this vessel. The vasodilation appears to be mediated by the EP4 receptor coupled to a cAMP-dependent mechanism.

What is the function of the prostaglandins? ›

The prostaglandins are a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness. They control processes such as inflammation, blood flow, the formation of blood clots and the induction of labour.

What is the important role of prostaglandins? ›

Prostaglandins play a key role in the generation of the inflammatory response. Their biosynthesis is significantly increased in inflamed tissue and they contribute to the development of the cardinal signs of acute inflammation.

What are three 3 possible treatments for PKD? ›

  • Careful control of blood pressure.
  • Prompt treatment with antibiotics for bladder or kidney infection.
  • Drinking lots of fluid when blood in the urine is first noted.
  • Medication to control pain (talk to your doctor about which over-the-counter medicines are safe to take if you have kidney disease)

How do you slow down polycystic kidney disease? ›

Controlling high blood pressure can delay the progression of the disease and slow further kidney damage. Combining a low-sodium, low-fat diet that's moderate in protein and calorie content with not smoking, increasing exercise and reducing stress may help control high blood pressure.

Which goal is a priority when caring for a patient with polycystic kidney disease? ›

If you or someone you care about is living with PKD, your top priorities are maintaining a high quality of life and managing the disease.

Why are ACE inhibitors preferred in CKD? ›

ACE inhibitors effectively reduce systemic vascular resistance in patients with hypertension, heart failure or chronic renal disease. This antihypertensive efficacy probably accounts for an important part of their long term renoprotective effects in patients with diabetic and non-diabetic renal disease.

How do ACE inhibitors work for CKD? ›

How does an ACE inhibitor work? ACE inhibitors prevent an enzyme in your body from producing angiotensin II, a substance that affects your cardiovascular system by narrowing your blood vessels and releasing hormones that can raise your blood pressure.

How do ACE inhibitors prevent proteinuria? ›

ACE inhibitors and ARBs reduce proteinuria by lowering the intraglomerular pressure, reducing hyperfiltration. These drugs tend to raise the serum potassium level and reduce the glomerular filtration rate (GFR). Monitoring the serum potassium and creatinine levels and the GFR is therefore imperative.

What do prostaglandins do to blood vessels? ›

Prostaglandins can: Activate or inhibit (prevent) platelet buildup for blood clot formation. Cause vasodilation (widening of blood vessels) or vasoconstriction (narrowing of blood vessels).

How do prostaglandins increase permeability? ›

Prostaglandins (E1, E2, F and F) evoke increased vascular permeability in the skin of rat and man7, which appears to be an indirect effect resulting from mast cell degranulation.

What are the prostaglandin receptors? ›

Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2, (i.e. PGD2), PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2 ...

What are the four functions of prostaglandins? ›

Prostaglandins play a role in the following reproductive functions: 1) conception; 2) luteolysis; 3) menstruation; and 4) parturition. It has also been proposed that Prostaglandin A may be the natriuretic hormone, the circulating hormone which controls sodium reabsorption by the kidney.

What are three uses of prostaglandins? ›

Abstract. PIP: Prostaglandins have found clinical applications in: 1) termination of midtrimester pregnancy; 2) induction of labor; 3) menstrual regulation; and 4) control of postpartum hemorrhage.

What is the mechanism of action of prostaglandins? ›

Mechanism of Action

[2] The COX-1 enzyme produces basal amounts of prostaglandins, while chemical mediators induce the COX-2 isoform to increase prostaglandins production. Prostaglandins are highly lipophilic molecules that enter cells via a special prostaglandin transporter called PGT (prostaglandin transporter).

What do prostaglandins protect in the body? ›

Prostaglandins are found in high concentration in the gastric mucosa and gastric juice. Exogenous prostaglandins inhibit acid secretion, stimulate mucus and bicarbonate secretion, alter mucosal blood flow, and provide dramatic protection against a wide variety of agents which cause acute mucosal damage.

What are examples of prostaglandins? ›

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What are prostaglandins and what is their function quizlet? ›

Prostaglandin. Are active lipids formed from arachidonic acid and act as short-lived paracrine and autocrine messengers. Cyclooxygenase. Makes prostaglandins from arachidonic acid. Phospholipase A2.

Can polycystic kidney disease reversed? ›

Using mouse models, researchers showed that, in early stages of polycystic kidney disease (PKD), kidney damage can be reversed by reactivating an inactive gene—findings that raise the possibility of using gene therapy to treat people with PKD.

Why does polycystic kidney disease cause brain aneurysm? ›

The aneurysmal walls are characterized by disruption of the elastic tissue and loss of vascular smooth muscle cells. A reduction in the level of polycystin in the vascular smooth muscle caused by the PKD mutations likely facilitates the development of the aneurysms.”

What is the best treatment for stage 3 kidney disease? ›

The more impactful symptoms of kidney disease stage 3 are the health implications of your decreased kidney functioning such as high blood pressure, anemia, and bone disease. If your kidneys fail, you will either need to have dialysis or a kidney transplant. Dialysis is a treatment that will clean your blood.

What makes polycystic kidney disease worse? ›

High blood pressure.

Elevated blood pressure is a common complication of polycystic kidney disease. Untreated, high blood pressure can cause further damage to your kidneys and increase your risk of heart disease and strokes.

What triggers polycystic kidney disease? ›

What causes PKD? A gene mutation, or defect, causes PKD. In most PKD cases, a child got the gene mutation from a parent. In a small number of PKD cases, the gene mutation developed on its own, without either parent carrying a copy of the mutated gene.

Can you drain polycystic kidneys? ›

If you have a large kidney cyst that is causing pain, a specialist radiologist can drain the fluid from it using a large needle. This is called percutaneous cyst aspiration. Your radiologist will use ultrasound or a CT (computed tomography) scan to guide the needle to the cyst.

What is the new treatment for PKD? ›

On April 24, 2018, the U.S. Food and Drug Administration approved Tolvaptan, the first-ever disease-modifying drug for ADPKD. Tolvaptan slows the growth of kidney cysts and prolongs kidney function.

At what GFR should ACE inhibitors be stopped? ›

Accordingly, in patients with CKD stage 5 (eGFR <15 mL/min per 1.73 m2), the guidelines recommend reducing the dose or discontinuing ACE inhibitors or ARBs in the setting of either symptomatic hypotension or uncontrolled hyperkalemia [1,2,3].

Which ACE inhibitor is good for patients with reduced kidney function? ›

The Ramipril Efficacy in Nephropathy study15 found a significantly higher GFR and a lower rate of GFR decline in patients without diabetes who received the ACE inhibitor ramipril than in similar patients who were given placebo.

At what creatinine level should ACE inhibitors be stopped? ›

The authors recommend that ACE inhibitor therapy should not be discontinued unless serum creatinine level rise above 30% over baseline during the first 2 months after initiation of therapy or hyperkalemia (serum potassium level >or=5.6 mmol/L) develops.

Why avoid ACE inhibitors in renal failure? ›

During ACEI initiation, renal dysfunction can occur due to a drop in renal perfusion pressure and subsequent decrease in glomerular filtration. This is attributed to the drug's preferential vasodilation of the renal efferent arteriole, which impairs the kidney's ability to compensate for low perfusion states.

Why do ACE inhibitors increase creatinine? ›

The rise in serum creatinine values usually begins a few days after beginning therapy with an ACE inhibitor or an ARB, as angiotensin II levels are rapidly reduced or blocked from binding. This results in efferent arteriolar dilatation and decreased effective GFR.

Do ACE inhibitors improve GFR? ›

In general, ACE-inhibition does not affect normal glomerular filtration rate (GFR) but may increase GFR in patients on a low sodium intake prior to treatment. Since the rise in GFR is smaller than the rise in renal blood flow, in most instances a decrease in filtration fraction will result.

How long does it take for ACE inhibitor to reduce proteinuria? ›

In patients with moderate proteinuria, ACE-I caused 44 +/- 6% reduction in proteinuria (from 2.7 +/- 0.5 to 1.5 +/- 0.4 g/day, n = 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 +/- 0.2 g/day).

Which ACE inhibitor is best for proteinuria? ›

Temocapril can be an option when practitioners are searching for more proteinuria reduction but less blood pressure variation. In normotensive diabetic nephropathy, monotherapy with the ACEI enalapril seems to be the most efficacious intervention for reducing albuminuria.

Why use ACE inhibitors for proteinuria? ›

ACE inhibitors also reduce the rate of progression of kidney disease, and the risk of dialysis or transplantation by up to 50% in patients with proteinuria. The angiotensin receptor antagonists are effective for reducing proteinuria in diabetic and non-diabetic populations.

What organ produces prostaglandins? ›

Prostaglandins were believed to be part of the prostatic secretions, and eventually were discovered to be produced by the seminal vesicles.

Are prostaglandins good or bad? ›

Prostaglandins can have healing effects, especially in the stomach. They decrease stomach acid production while also stimulating the release of protective mucus in the GI tract. In addition, prostaglandins also influence blood clotting to prevent bleeding. They also help dissolve clots when a person is healing.

Do kidneys produce prostaglandins? ›

Various kidney cells produce prostaglandins: tubular epithelial cells, renal medullary interstitial cells, and cells of the glomeruli (Dunn, 1977). The main sites of prostaglandin synthesis occurs in the medullary tissue of the kidney, established by medullary slices or isolated cell preps (Bonvalet, 1987).

What stimulates prostaglandin release in kidney? ›

It is activated selectively by cicaprost and iloprost3, 5), which vasodilate renal arterioles and inhibit water permeability of the cortical collecting ducts5).

What reduces prostaglandin production? ›

Ketoprofen, a cyclooxygenase inhibitor, reduces prostaglandin production, whereas previous exercise in the placebo trial would elicit increases in prostaglandins.

What causes high prostaglandins? ›

The more estrogen-based foods you consume, the more likely your uterine lining becomes abnormally thick. As a result, when it begins to break down during the menstrual cycle, this process creates more prostaglandins, resulting in higher levels of pain.

What are the 4 types of prostaglandins? ›

There are four principal bioactive prostaglandins generated in vivo: prostaglandin (PG) E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2) and prostaglandin F (PGF).

What are the 9 function of prostaglandins? ›

Functions of Prostaglandins

Activation of the inflammatory response, production of pain, and fever. When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result. Blood clots form when a blood vessel is damaged.

What are the 5 prostaglandins? ›

They are synthesised in the bladder by cyclooxygenase (COX) and then subsequently converted into five primary prostanoids via their respective synthases: PGE2, PGD2, PGF, prostacyclin (PGI2) and thromboxane (TXA2) [9].

What are the four effects of prostaglandins? ›

Prostaglandins can: Activate or inhibit (prevent) platelet buildup for blood clot formation. Cause vasodilation (widening of blood vessels) or vasoconstriction (narrowing of blood vessels). Cause bronchoconstriction (the narrowing of air passageways) or bronchodilation (widening of air passageways).

When is prostaglandins released in kidney? ›

In response to ischemia, vasoconstriction, or angiotensin II the kidney increases prostaglandin synthesis to modulate renal vascular resistance.

What effect does prostaglandin have on the bladder? ›

The urinary bladder U&LP and detrusor respond to a variety of prostaglandin agonists, with their activation resulting in direct contractions, as well as increases to spontaneous contractile activity.

How do NSAIDs cause kidney damage? ›

NSAIDs disrupt the compensatory vasodilation response of renal prostaglandins to vasoconstrictor hormones released by the body [5]. Inhibition of renal prostaglandins results in acute deterioration of renal function after ingestion of NSAIDs.

What are the problems with prostaglandins? ›

Individuals may experience health problems if their prostaglandin level is too high or too low. Excessive prostaglandins may lead to painful periods and heavy menstrual bleeding, whereas low levels can contribute to stomach ulcers and glaucoma.

What prostaglandins are synthesized in the kidneys? ›

In the cortex, major sites of prostaglandin synthesis include arteries and arterioles as well as the glomerulus. At these sites, prostaglandins are important in maintaining blood flow and glomerular filtration, especially during conditions of enhanced vasoconstrictor activity.

What triggers prostaglandin production? ›

Stressors including tissue damage, infection and illness can all trigger more prostaglandins to be produced. They are also produced to help contract the uterus in order to bring on menstruation and labor.

How does prostaglandin reduce blood pressure? ›

Abstract. In normotensive and hypertensive humans, prostaglandins, particularly PGE2 and PGI2, affect blood pressure through control of vascular resistance, salt excretion, cardiac output, and renin secretion.

What are the positive effects of prostaglandins? ›

Prostaglandins can have healing effects, especially in the stomach. They decrease stomach acid production while also stimulating the release of protective mucus in the GI tract. In addition, prostaglandins also influence blood clotting to prevent bleeding. They also help dissolve clots when a person is healing.

Does diuretics increase prostaglandin? ›

A prostaglandin mechanism may contribute to the action of those diuretic agents which increase levels of PGE2 i n the renal medulla.

How do prostaglandins affect ADH? ›

Prostaglandins influence the action of ADH and it is likely that in life they regulate and modulate the change in water permeability induced by anti-diuretic hormone.

Why should people with kidney disease avoid NSAIDs? ›

These medications should only be used under a doctor's care by patients with kidney disease, heart disease, high blood pressure or liver disease or by people who are over 65 or who take diuretic medications. NSAIDs may cause an increased risk of sudden kidney failure and even progressive kidney damage.

Which anti-inflammatory is best for kidneys? ›

A gel form of the prescription NSAID diclofenac (Voltaren Gel) is one option. Only a very small amount of the drug gets into the bloodstream, so it may be safe for your kidneys.

Why should NSAIDs be avoided in kidney disease? ›

NSAID therapy causes a number of adverse effects in the kidney through inhibition of prostaglandin production. Abbreviations: AKI, acute kidney injury; ATI, acute tubular injury; CHF, congestive heart failure; GFR, glomerular filtration rate; HTN, hypertension; RTA, renal tubular acidosis.


1. UCSF Polycystic Kidney Disease Center of Excellence
2. Polycystic Kidney Disease
(AETCM Emergency Medicine)
3. Polycystic Kidney Disease (PKD) | Anjay Rastogi, MD | UCLAMDChat
(UCLA Health)
4. Diet Strategies for Polycystic Kidney Disease
5. Frontiers in Autosomal Polycystic Kidney Disease (ADPKD) | Peter Harris, PhD
(UCLA Health)
6. New drug targets common kidney disease


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