Renal Prostaglandin Research Articles

Furosemide and Ductus Arteriosus Closure in Very-Low-Birth-Weight Preterm Infants: A Comprehensive Retrospective Study.

Ductus arteriosus closure may be delayed in preterm infants, and prostaglandin, a vasodilator, can affect ductal patency. Furosemide can increase renal prostaglandin synthesis, so its net effect on patent ductus arteriosus (PDA) is uncertain. Our goal is to explore the relationship between furosemide and spontaneous ductal closure in very-low-birth-weight preterm infants. Our treatment for PDA involves fluid restriction initially and furosemide administration for hemodynamically significant PDA until closure is confirmed by the echocardiogram. We enrolled 105 infants from 1 January 2019 to 30 June 2022 and evaluated the impact of furosemide on ductal closure, including exposure duration and cumulative dose. There is no correlation between furosemide exposure and spontaneous ductal closure (p = 0.384). Furosemide exposure does not delay the postmenstrual age at which spontaneous ductal closure occurs (p = 0.558). The time for spontaneous ductal closure is positively associated with furosemide prescription days (coefficient value = 0.547, p = 0.026) and negatively with gestational age (coefficient value = -0.384, p = 0.062). The prescription of furosemide does not impact the probability or time duration of ductus arteriosus spontaneous closure. The cumulative dose of furosemide has minimal impact on ductal closure. The correlation between furosemide exposure duration and ductal patency duration is likely due to our treatment protocol, with gestational age being a significant factor.

Tissue lipidomic profiling supports a mechanistic role of the prostaglandin E2 pathway for albuminuria development in glomerular hyperfiltration.

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. The Munich Wistar Frömter (MWF) rat is a non-diabetic model of chronic kidney disease (CKD) with GH due to inherited low nephron number resulting in spontaneous albuminuria and podocyte injury. In MWF rats, we identified prostaglandin (PG) E2 (PGE2) signaling as a potential causative mechanism of albuminuria in GH. Method: For evaluation of the renal PGE2 metabolic pathway, time-course lipidomic analysis of PGE2 and its downstream metabolites 15-keto-PGE2 and 13-14-dihydro-15-keto-PGE2 was conducted in urine, plasma and kidney tissues of MWF rats and albuminuria-resistant spontaneously hypertensive rats (SHR) by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Results: Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE2 and 15-keto-PGE2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE2 levels. Glomerular metabolic ratios of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were significantly lower, while metabolic ratios of prostaglandin reductases (PTGRs) were significantly higher in MWF rats with manifested albuminuria compared to SHR, respectively. Conclusion: Our data reveal glomerular dysregulation of the PGE2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE2 degradation. This study provides first insights into dynamic changes of the PGE2 pathway that support a role of glomerular PGE2 metabolism and signaling for early albuminuria manifestation in GH.

The Epigenetic Legacy of Maternal Protein Restriction: Renal Ptger1 DNA Methylation Changes in Hypertensive Rat Offspring.

Nutrient imbalances during gestation are a risk factor for hypertension in offspring. Although the effects of prenatal nutritional deficiency on the development of hypertension and cardiovascular diseases in adulthood have been extensively documented, its underlying mechanisms remain poorly understood. In this study, we aimed to elucidate the precise role and functional significance of epigenetic modifications in the pathogenesis of hypertension. To this end, we integrated methylome and transcriptome data to identify potential salt-sensitive hypertension genes using the kidneys of stroke-prone spontaneously hypertensive rat (SHRSP) pups exposed to a low-protein diet throughout their fetal life. Maternal protein restriction during gestation led to a positive correlation between DNA hypermethylation of the renal prostaglandin E receptor 1 (Ptger1) CpG island and high mRNA expression of Ptger1 in offspring, which is consistently conserved. Furthermore, post-weaning low-protein or high-protein diets modified the Ptger1 DNA hypermethylation caused by fetal malnutrition. Here, we show that this epigenetic variation in Ptger1 is linked to disease susceptibility established during fetal stages and could be reprogrammed by manipulating the postnatal diet. Thus, our findings clarify the developmental origins connecting the maternal nutritional environment and potential epigenetic biomarkers for offspring hypertension. These findings shed light on hypertension prevention and prospective therapeutic strategies.

Evaluation of Renoprotective Effect of Lipoic Acid and Bosentan Against Diclofenac-Induced Acute Renal Failure

Acute renal failure also known as acute kidney injury (AKI) is a complex health condition related to significant morbidity and mortality. In hospitalized patients, around 19-33 percent of AKI episodes are linked to drug induced nephrotoxicity. Although considered safe, NSAIDs such as diclofenac have gained special attention over the past few years due to the potential risk of renal injury. The direct effect of diclofenac-induced renal injury depends on targeting the mitochondria in kidney tissue, and formation of reactive oxygen species (ROS) resulting in oxidative stress. Secondly, diclofenac inhibit renal prostaglandin production, limiting renal afferent arteriole vasodilation, increasing afferent resistance; thus decreasing the glomerular capillary pressure below normal values and glomerular filtration rate will decrease resulting in AKI. Alpha-Lipoic acid (ALA) has beneficial effects in prevention or relief of symptoms of oxidative stress- related diseases, as it acts as antioxidant and anti-inflammatory micronutrient. Bosentan is a competitive antagonist with dual endothelin-1 receptors, as renal vascular ET-1 system is upregulated under many pathophysiological situations. In present study, we investigated the effect of lipoic acid and bosentan in diclofenac induced acute renal failure in male rats.
 We observed that diclofenac increased serum levels of urea, creatinine, malondialdehyde, KIM-1, TGFβ1 and fibronectin significantly (p>0.05) in the induction group compared to control group. While, SOD significantly (p>0.05) reduced in the induction group compared to control group. Both of lipoic acid and bosentan alone didn’t significantly protect against diclofenac induced AKI. However, the combination group showed a significant protection against AKI. Pearson correlation analysis showed a significant positive correlation between (urea and KIM-1) and between (creatinine and KIM-1) (r2=0.792 and r2=0.677 respectively). Furthermore, there was a significant positive correlation between fibronectin and urea (r2= 0.498, p>0.01) and fibronectin and creatinine (r2=0.356, p>0.05). Interestingly, KIM-1 showed a significant positive correlation with fibronectin (r2=0.536, p>0.01).
 ROC curve test was performed for KIM-1 and fibronectin biomarkers. The AUC for KIM-1 was 0.986 and for fibronectin was 0.829. We concluded that combination therapy of lipoic acid and bosentan showed a significant protective effect against diclofenac-induced AKI. In addition, fibronectin could be a promising biomarker for detection and diagnosis of acute kidney injury.
 Key words: Diclofenac, oxidative stress, alpha- lipoic acid, endothelin-1, bosentan

PS-R04-1: A CASE OF DRUG-INDUCED RENAL INJURY AND DRUG-INDUCED HYPERTENSION RESULTING IN HYPERTENSIVE EMERGENCIES

48 years old male. He had high blood pressure for 2 years and was treated at a Chinese herbal medicine shop, the prescription was changed each time. He began to have headaches and was taking triple doses of NSAIDs daily. Three months later, he developed lightheadedness and edema. He was diagnosed with hydrocephalus, Ommaya reservoir was inserted, but his loss of consciousness was prolonged. He was transferred to the neurosurgery department of our hospital on X + 3 for close examination of the tumor. At the time of transfer, his Cr was 9.32 mg/dl and he was referred to our department. He was suspected to have uremic symptoms, so Hemodialysis (HD) was started. Renal biopsy revealed nephrosclerosis and drug-induced kidney injury (DKI). Since the previous physician had discontinued NSAIDs and Chinese herbal medicine, so we mainly managed him with antihypertensive therapy. The Neurosurgical examination was negative for tumor, and the patient was transferred to the Department of Neurology on X + 11 for further examination of encephalopathy. Although his blood pressure was 230/140 mmHg immediately after transfer, the presence of endocrine hypertension was excluded, and the symptom improved by the elimination of the uremia and lowering of the blood pressure by ARB, CCB and HD. In addition, extensive white matter lesions on head CT resolved, so he was diagnosed Posterior reversible encephalopathy syndrome (PRES). He was weaned from HD on X + 29 after his urinary output recovered, but was transferred to our department on X + 31 for decision making including reintroduction of HD because of his Cr 5.08 mg/dl level. He was discharged from the hospital on X + 47 after starting half-pulse steroid therapy (0.5 mg/kg post therapy) for DKI, with a strong desire to avoid reintroduction of HD. Currently, his Cr is 2.87 mg/dl. This case of hypertensive emergency was caused by DKI and drug-induced hypertension. NSAIDs suppress renal prostaglandin production by inhibiting COX, resulting in decreased renal function and increased blood pressure. Although the details of the Chinese herbal remedy are unknown, we suspected that NSAIDs was the cause of the hypertension, because the RAA system is usually suppressed if licorice is the cause. Although the rate of conversion from hypertensive emergencies to maintenance dialysis has not been shown, it is considered that the early release of renal load by HD in this case led to the recovery of renal function.

Salbutamol for analgesia in renal colic: study protocol for a prospective, randomised, placebo-controlled phase II trial (SARC)

BackgroundRenal colic is the pain experienced by a patient when a renal calculus (kidney stone) causes partial or complete obstruction of part of the renal outflow tract. The standard analgesic regimes for renal colic are often ineffective; in some studies, less than half of patients achieve complete pain relief, and a large proportion of patients require rescue analgesia within 4 h. Current analgesic regimes are also associated with significant side effects including nausea, vomiting, drowsiness and respiratory depression. It has been hypothesised that beta adrenoreceptor agonists, such as salbutamol, may reduce the pain of renal colic. They have been shown to impact a number of factors that target the physiological causes of pain in renal colic (ureteric spasm and increased peristalsis, increased pressure at the renal pelvis and prostaglandin release with inflammation). There is biological plausibility and a body of evidence sufficient to suggest that this novel treatment for the pain of renal colic should be taken to a phase II clinical trial. The aim of this trial is to test whether salbutamol is an efficacious analgesic adjunct when added to the standard analgesic regime for patients presenting to the ED with subsequently confirmed renal colic.MethodsA phase II, randomised, placebo-controlled trial will be performed in an acute NHS Trust in the East Midlands. Patients presenting to the emergency department with pain requiring IV analgesia and working diagnosis of renal colic will be randomised to receive standard analgesia ± a single intravenous injection of Salbutamol. Secondary study objectives will explore the feasibility of conducting a larger, phase III trial.DiscussionThe trial will provide important information about the efficacy of salbutamol as an analgesic adjunct in renal colic. It will also guide the development of a definitive phase III trial to test the cost and clinical effectiveness of salbutamol as an analgesic adjunct in renal colic. Salbutamol benefits from widespread use across the health service for multiple indications, extensive staff familiarity and a good side effect profile; therefore, its potential use for pain relief may have significant benefits for patient care.Trial registrationISRCTN Registry ISRCTN14552440. Registered on 22 July 2019

Blockade of Microglial Activation in Hypothalamic Paraventricular Nucleus Improves High Salt-Induced Hypertension.

It has been shown that activated microglia in brain releasing proinflammatory cytokines (PICs) contribute to the progression of cardiovascular diseases. In this study, we tested the hypothesis that microglial activation in hypothalamic paraventricular nucleus (PVN), induced by high-salt diet, increases the oxidative stress via releasing PICs and promotes sympathoexcitation and development of hypertension. High-salt diet was given to male Dahl salt-sensitive rats to induce hypertension. Those rats were bilaterally implanted with cannula for PVN infusion of minocycline, a selective microglial activation blocker, or artificial cerebrospinal fluid for 4 weeks. High-salt diet elevated mean arterial pressure of Dahl salt-sensitive rats. Meanwhile, elevations of renal sympathetic nerve activity and central prostaglandin E2, as well as increase of plasma norepinephrine, were observed in those hypertensive rats. Tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 increased in the PVN of those rats, associated with a significant activation of microglia and prominent disruption of redox balance, which was demonstrated by higher superoxide and NAD(P)H oxidase 2 (NOX-2) and NAD(P)H oxidase 4 (NOX-4), and lower Cu/Zn superoxide dismutase in PVN. PVN infusion of minocycline attenuated all hypertension-related alterations described above. This study indicates that high salt leads to microglial activation within PVN of hypertensive rats, and those activated PVN microglia release PICs and trigger the production of reactive oxygen species, which contributes to sympathoexcitation and development of hypertension. Blockade of PVN microglial activation inhibits inflammation and oxidative stress, therefore attenuating the development of hypertension induced by high-salt diet.

Involvement of NOX-4/JAK/STAT pathway in the protective effect of aprepitant against diclofenac-induced renal toxicity

AimsAprepitant, a neurokinin-1 (NK1) receptor antagonist, is a clinically approved anti-emetic drug. Recently, inhibition of the NK1 receptor has been reported as a potential nephroprotective strategy. We aimed to assess the pharmacological mechanisms of aprepitant against diclofenac (DIC)-induced renal toxicity. Main methodsAn in vivo study was conducted using twenty-four male Wistar rats, divided into 4 groups. Aprepitant was administered for 5 days (5 mg/kg/day) with or without DIC which was given on the 4th and 5th days (50 mg/kg, i.p.). At the end of the study, renal function biomarkers, renal oxidative parameters, prostaglandin E (PGE-2), and NADPH oxidase (NOX-4) were measured. Histopathological changes as well as expression of renal inflammatory and apoptotic markers (tumor necrosis factor alpha (TNF-α) and caspase-3) were investigated. Key findingsDIC caused significant renal damage, as evidenced by deterioration of renal functions, oxidative stress, inflammatory and apoptotic markers, and confirmed by histopathological findings. Pretreatment with aprepitant successfully ameliorated and improved all biochemical and molecular parameters induced by DIC. Moreover, aprepitant restored the decrease in renal PGE-2 concentration and inhibited DIC-activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling in renal tissues. SignificanceThe protective effect of aprepitant is possibly attributed to its anti-oxidant and anti-inflammatory roles via the NOX-4/JAK/STAT pathway.

Cyclooxygenase-2 contributes to diabetic nephropathy through glomerular EP4 receptor

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and the leading cause of mortality in diabetic patients. Cyclooxygenase (COX) and COX-derived prostanoids are documented to participate in the pathogenesis of diabetic nephropathy. Herein, we found an increased COX2 expression level in diabetic kidneys of STZ-induced DBA mice. The COX2 inhibitor significantly attenuated albuminuria and histological lesions, accompanied by up-regulation of the renal angiopoietin-1/tie-2 system. This finding is consistent with the presence of an angiogenic signature in endothelial cells during the development of DN. Prostaglandin E2 (PGE2) is the most abundant prostanoid in the kidney, and its receptor EP4 is expressed in the glomerulus, as determined by in situ hybridization. To test the hypothesis that diabetes-associated COX2 overexpression induces renal PGE2 production and endothelial dysfunction by activating glomerular EP4 receptors, the effect of an EP4 antagonist on Akita/DBA mice was investigated. Our results showed that blockade of EP4 receptor significantly reduced albuminuria in diabetic mice. Owing to the established adverse effect of COX2 inhibitors, our study provided new insight into meaningful renal benefits for diabetic nephropathy by targeting the EP4 receptor.

MO431LIPIDOMIC ANALYSIS IN A NON-DIABETIC RAT MODEL WITH HYPERFILTRATION AND ALBUMINURIA REVEALS DYNAMIC CHANGES IN THE PROSTAGLANDIN E2 PATHWAY DURING ONSET OF ALBUMINURIA AS A POTENTIAL CAUSATIVE MECHANISM

Abstract Background and Aims We recently identified prostaglandin reductase 2 (Ptgr2) and the prostaglandin E2 (PGE2) pathway as potential causative mechanism in the Munich Wistar Frömter (MWF) non-diabetic rat model of chronic kidney disease. MWF is characterized by early onset of spontaneous albuminuria during a critical time window between 4 and 8 weeks of age, that associates with hyperfiltration, due to low nephron number, and podocyte injury. Ptgr2 plays an important role in the prostaglandin metabolism, in which PGE2 is metabolized by 15-prostaglandin dehydrogenase (15-PGDH) to 15-keto-PGE2. The latter is terminally degraded by prostaglandin reductases (PTGRs) 1, 2, and 3 to 13,14-dihydro-15-keto-PGE2. Recently, we detected elevated glomerular levels of PGE2 and 15-keto-PGE2 in MWF compared to spontaneously hypertensive rats (SHR) with no albuminuria. The aim of the present study was to characterize in detail the renal PGE2 metabolic pathway in MWF by lipidomic analysis during the time window of albuminuria onset. Method Male MWF and SHR rats were studied at week 4 and 8, respectively; 24 h-urine was collected in metabolic cages. In addition, plasma and kidney tissues including kidney cortex and isolated glomeruli were obtained from anesthetized rats. Lipidomic analysis was done by liquid chromatography electrospray ionization tandem mass spectrometry. Statistical analysis was performed by unpaired, two-tailed Student’s t-test, or otherwise the Mann-Whitney test. Results Urinary PGE2 was significantly lower (p<0.01), while urinary 15-keto-PGE2 and 13,14-dihydro-15-keto PGE2 levels were significantly increased in MWF compared to SHR at week 4 (p<0.01, respectively). All three analytes were significantly decreased in urine of MWF with increased albuminuria at week 8 (p<0.05 vs. SHR). The urinary metabolic ratio of 15-keto-PGE2/13,14-dihydro-15-keto-PGE2 as a surrogate for PTGRs activities was significantly increased at week 4 (p<0.01), whereas it was significantly decreased in MWF vs. SHR at week 8 (p<0.05). Plasma levels of PGE2 and 13,14-dihydro-15-keto-PGE2 did not differ between strains at both time points, while 15-keto-PGE2 was below the detection limit. Glomerular levels of PGE2 and 15-keto-PGE2 were increased in MWF at week 4 and 8 (p<0.01, respectively). In contrast, 13,14-dihydro-15-keto-PGE2 was only significantly higher at week 4 compared to SHR (p<0.01). In isolated glomeruli, the metabolic ratios of PTGRs were similar between the strains at week 4, but significantly increased in MWF compared to SHR at week 8 (p<0.01, respectively). In kidney cortex, 15-keto-PGE2 and 13,14-dihydro-15-keto-PGE2 were increased in MWF at week 4 (p<0.05 and p<0.01, respectively), whereas PGE2 levels were comparable to SHR. No difference for cortical levels of PGE2 and its metabolites was observed at week 8. Conclusion This study provides the first insights into age-dependent dynamic changes in the PGE2 pathway that support potential causality for the onset of albuminuria in the setting of non-diabetic hyperfiltration due to low nephron number. Notably, the increased glomerular levels of PGE2 and its downstream metabolites in 4-week-old MWF point towards an early activation of this pathway, i.e. before albuminuria occurs. This finding corroborates the hypothesis that glomerular PGE2 signaling is relevant in the early stages of hyperfiltration and suggests this pathway as a target for future therapeutics to modify the manifestation and progression of renal disease.

Protective role of Oleuropein, an olive tree secoiridoid and its acyl-derivate in experimental models of rheumatic diseases

Oleuropein (OL), an olive tree secoiridoid, and its peracetylated derivate (Per-OL) have exhibited several beneficial effects reducing acute inflammatory responses on LPS-stimulated macrophages. The present study was designed to evaluate the effects of both dietary OL and Per-OL supplementations on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with 0.05% (w/w) OL, 0.05% or 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and mice received a booster injection on day 21. Mice were sacrificed 42 days after first immunization. Then, blood was recollected and paws were histological and biochemically processed. OL and Per-OL experimental diets significantly prevented histological damage and arthritic score development in RA. In addition, serum collagen oligomeric matrix protein (COMP) and metalloproteinase 3 (MMP)-3 as well as proinflammatory cytokines levels in paw homogenates (including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and interferon (IFN)-γ were significantly ameliorated in those animals fed with dietary secoiridoids. Mitogen-activated protein kinases (MAPKs) and nuclear transcription factor kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions were significantly up-regulated in those mice fed with OL and Per-OL diets. These results reveal, for the first time, the anti-inflammatory effect of a diet supplemented with OL and Per-OL in an experimental murine model of CIA, which was accompanied by a significant reduction in the pro-inflammatory markers studied (COMP, MMP-3, TNF-α, IL-1β, IL-6, IL-17 and IFN-γ). The mechanisms involved could be related to an activation of the antioxidant pathway Nrf2/HO-1 and an inhibition of MAP kinases and NF-κB signaling pathways activations. On the other hand, we studied the effects of both OL and Per-OL diets supplemented diets in a model of pristane-induced systemic lupus erythematosus (SLE) in BALB / c mice. Mice received an intraperitoneal injection of pristane or saline according to the experimental groups and were fed with experimental diets enriched with OL and Per-OL. Changes in cytokines levels and pro-inflammatory markers were evaluated by the ELISA assay. Changes in the protein expression of inducible nitric oxide synthase (iNOS), microsomal prostaglandin E synthase 1 (mPGEs-1) as well as HO-1, nuclear factor Nrf2, p38 protein kinases, C-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), signal transduction factor and activator of transcription (STAT) -3, NF-κB and inflammasome NLRP3 activation were determined using the Western Blot. Both OL and Per-OL dietary treatments significantly reduced kidney damage and reduced serum MMP-3 and renal prostaglandin E2 (PGE2) levels. Our studies indicated that OL and Per-OL enriched diets produced an increase in the expression of the antioxidant pathway Nrf2 / HO-1 which was accompanied by a decrease in the activation of the Janus kinases and signal transducer and activator of transcription (JAK / STAT), MAPKs, NF-κB and inflammasome NLRP3 proteins. In conclusion, dietary supplementation with OL and Per-OL could serve as the basis for the development of new nutritional strategies for the prevention of RA. In addition, these results also suggest that dietary supplementation with OL and Per-OL could constitute a new alternative therapeutic approach as a preventive or palliative of nephritis in the management of SLE.

P0522INHIBITING 15-PGDH PREVENTS ISCHEMIC RENAL INJURY BY A PGE2/EP4 SIGNALING PATHWAY MEDIATING VASODILATION, INCREASED RENAL BLOOD FLOW, AND INCREASED ADENOSINE/A2A RECEPTOR

Abstract Background and Aims We demonstrate the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia reperfusion injury (IRI). AKI due to ischemic injury represents a significant clinical problem. Prostaglandin E2 (PGE2) is vasodilator in the kidney, but is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Method 10-week aged male C57/BL6 mice were randomly allocated to five groups (n=8 to 15 in each group): the sham-control group, sham-SW033291 group, IRI-vehicle group, IRI-indomethacin group and the IRI-SW033291 group. IRI were induced by clamping bilateral renal artery for 30 min followed by 24 hours of reperfusion. Vehicle, indomethacin, or SW033291 were intraperitoneally administered three times at 1 hour before, immediately after, and 12 hours after IRI. Renal function, histological changes, and renal blood flow were compared and the relevant parameters of oxidative stress and inflammation were detected. Results Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI histologic injury score and tubular apoptosis and markedly reduced biomarkers of renal injury that included BUN, creatinine, NGAL and KIM-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high mobility group box 1 (HMGB1), and malondialdehyde (MDA). Protective effects of SW033291 were mediated by PGE2 signaling as they could be blocked by pharmacologic inhibition of PGE2 synthesis or of the EP4 type PGE2 receptor. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 and of cyclic adenosine monophosphate (cAMP), along with other vasodilatory effectors including AMP, adenosine, and the adenosine A2A receptor (A2A). Protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Conclusion Inhibiting 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

Bartter's syndrome: clinical findings, genetic causes and therapeutic approach.

Bartter's syndrome (BS) is a rare group of salt losing tubulopathies due to the impairment of transport mechanisms at the thick ascending limb of the Henle's loop. Literature reviews and original research articles were collected from database, including PubMed and Scopus. According to the time of onset and symptoms, BS can be classified into antenatal and classic BS. Molecular studies have identified different subtypes of BS. BS types I, II and III are caused by mutations on genes encoding the luminal Na+-K+-2Cl- co-transporter, the luminal K+ channel ROMK, and the basolateral chloride channel ClC-Kb (CLCNKB), respectively. Loss-of-function mutations of Barttin CLCNK type accessory beta subunit cause BS type IVa. Simultaneous mutations of CLCNKB and CLCNKA cause BS type IVb. BS type V consists in a novel transient form characterized by antenatal presentation due to mutations in the MAGE family member D2. Severe gain-of-function mutations of the extracellular calcium sensing receptor gene can result in an autosomal dominant condition of BS. Main clinical and biochemical alterations in BS include polyuria, dehydration, hypokalemia, hypochloremic metabolic alkalosis, hyperreninemia, high levels of prostaglandins, normal or low blood pressure, hypercalciuria and failure to thrive. Treatment focuses mainly at correcting dehydration and electrolyte disturbances and in measures to reduce polyuria, including the use of nonsteroidal anti-inflammatory medications to control excessive renal prostaglandin E2 production. Early diagnosis and treatment of BS may prevent long-term consequences such as growth failure, nephrocalcinosis and end-stage renal disease.

Clinico-genetic specifications of Bartter and Gitelman syndrome in children

Molecular genetic research has led to the discovery of new genes encoding proteins – transporters, cotransporters and exchangers involved in the transport of sodium, potassium and chlorine in the thick ascending part of the Henle loop and in the distal convoluted tubule. The article presents modern literature data on the genetic types of tubulopathy with the leading syndrome of hypokalemia and alkalosis – Bartter and Gitelman syndromes in children. The clinical and genetic features of the six types of Bartter syndrome with autosomal recessive and X-linked inheritance, classification approaches, diagnosis, and modern treatment methods are described. Since the first description of Bartter syndrome, 6 clinical genetic options have been known, including antenatal I, II, IVa, IVb, V types, which are potentially life-threatening diseases. Bartter type III syndrome is characterized by the manifestation of hypokalemic alkalosis in children at an early and preschool age. Treatment of Bartter syndrome in children includes the correction of water – electrolyte disturbances, the use of non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit the excessive formation of renal prostaglandin PgE 2. Gitelman syndrome with an autosomal recessive type of inheritance manifests itself in children at school age, later on in adolescents and adults there is an increase in clinical manifestations (with severe hypomagnesemic seizures of the upper and lower extremities, arterial hypertension) requiring correction. The review presents the clinical and genetic features of the rare, atypical form of the autosomal recessive Gitelman syndrome with a manifestation in school age, which is characterized by progressive bilateral calcifications of the subcortical parts of the cerebral hemispheres, calcifications in the basal ganglia and subcortical cerebellum. Unlike Bartter syndrome, with more severe clinical manifestations in newborns, infants and young children, Gitelman syndrome tends to increase clinical manifestations in adolescents and adults. Treatment of Gitelman syndrome in children and adolescents includes the correction of water – electrolyte disturbances, the use of magnesium preparations and salt subsidy.

Acute and Chronic Effects of Prostaglandin E2 on NKCC2, NCC and ENaC in Ex Vivo Renal Tubules

The major renal prostaglandin, prostaglandin E2 (PGE2), is enzymatically generated from arachidonic acid in a series of steps catalyzed by various enzymes including Cox1/2. PGE2 has modulatory effects on renal Na+ handling, but the molecular targets of these effects in the distal segments of the renal tubule (TAL, DCT, CD) are less well characterized. Here, we assessed acute (30 minutes) and long‐term (24 h) actions of PGE2 (0.1 nM to 10 μM) on various Na+ transport proteins in these segments using tubule suspensions isolated from mouse kidney. In the long‐term, no significant effects could be detected on the abundance of the NaCl cotransporter NCC, the Na‐K‐Cl cotransporter NKCC2 or the epithelial Na+ channel ENaC (αENaC). Altered phosphorylation of NCC (T58) and NKCC2 (T105) or proteolytic cleavage of αENaC was not observed. Similar results were obtained in the presence of Cox1/2 inhibition and no sex differences were observed. Acutely, no effects on NKCC2 or αENaC were observed, but phosphorylation of NCC was decreased. A similar decrease in NCC phosphorylation was detected in NCC‐expressing MDCK cells. Data mining of online kidney RNAseq databases suggested that prostanoid receptor EP4 was expressed in the DCT, and ongoing studies are centered on determining if the actions of PGE2 on NCC are via this receptor.Support or Funding InformationThis project has received funding from The European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska‐Curie grant agreement no 754513, The Aarhus University Research Foundation and NNF Laureate Research Grant ‐ Novo Nordisk Fonden

ER-depletion lowering the 'hypothalamus-uterus-kidney' axis functions by perturbing the renal ERβ/Ptgds signalling pathway.

Researchers have long assumed that systematic estrogen fading might contribute to the sustained progression of menopausal degenerate syndromes, although definitive evidence has not been presented. Whether such findings represent a causal contribution or are the result of opportunistic messengers sent from the reproductive system to the brain is also a vital question. We constructed a multiscale network of the ovariectomy (OVX) induced estrogen receptors depletion (ER-depletion) model and integrated targeted proteomic, targeted lipidomic, cytochemical, and histopathological data across three tissues from the ovariectomy rodent model. We found that compared to control rats, OVX rats showed increased renal and uterine prostaglandin D2 synthase (Ptgds) expression and decreased hypothalamic Ptgds expression, abnormal Ptgds metabolites, the degenerate renal function profiles and decreased cognitive ability (learning and memory) in Morris water maze test. Importantly, we observed a regulatory relationship among ER (particularly ERβ), the degree of the pathological phenotype, learning behavior test and the ‘hypothalamus-uterus-kidney (HUK) axis functions. Collectively, this study elucidates that ER depletion promoted HUK aging is mostly attributed to a renal ERβ/Ptgds signalling imbalance.

Renoprotective effects of the novel prostaglandin EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized chronic kidney disease rats.

Prostaglandins (PGs) are important lipid mediators of numerous physiologic and pathophysiologic processes in the kidney. PGE2, the most abundant renal PG, plays a major role in renal physiology, including renin release and glomerular hemodynamics. We investigated the renoprotective properties of the novel PGE2 EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized rats, a chronic kidney disease (CKD) model. Eight weeks of repeated administration of ASP7657 (0.001-0.1mg/kg) dose-dependently and significantly reduced urinary protein excretion and attenuated the development of glomerulosclerosis and tubulointerstitial damage, including fibrosis and inflammatory cell infiltration, without affecting blood pressure. Additionally, ASP7657 tended to have beneficial effects on renal function, as indicated by the decrease in plasma creatinine and blood urea nitrogen levels and attenuation of the decline in creatinine clearance (Ccr). The angiotensin II receptor blocker losartan (10mg/kg) also showed these renoprotective effects while significantly reducing blood pressure. ASP7657 dose-dependently and significantly reduced the EP4 receptor agonist-induced increase in plasma renin activity, as assessed by angiotensin I release in normal rats. Additionally, ASP7657 attenuated hyperfiltration assessed by Ccr without changing the renal blood flow or blood pressure in diabetic rats. These results suggest that ASP7657 suppresses the progression of chronic renal failure by modulating renin release and improving renal hemodynamics, and may therefore be a promising therapeutic option for inhibiting the progression of CKD.

NSAIDs and heart failure: A dangerous relationship.

One of the potential cardiotoxic action of anti-inflammatory drugs is the occurrence of heart failure (HF), due to their effects on fluid retention and blood pressure. The risk of hospitalization for HF is roughly doubled for both Coxibs, cyclooxygenase-1 (COX-1) and cyclooxygenase- 2 (COX-2) inhibitors, and all the conventional nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are also associated with a risk of vascular thrombosis, which for NSAIDs is different in relation to their different ability to inhibit COX-1 and COX-2. The cardiovascular toxicity of these drugs in the direction of HF follow different pathways respect to their related vascular thrombosis toxicity and involves, in particular, the renal prostaglandins, PGE2 and prostacyclin, mostly synthesized by COX-2. In the kidneys the PGs perform a direct vasodilatory action, e.g. by means of non-contrasting angiotensin mechanisms, and for this reason nimesulide effects on renal microcirculation are independent from the prevalence of intrarenal renin angiotensin aldosterone system (RAAS) activity. Conversely, nimesulide reduces sodium tubular urinary flow only in presence of intrarenal RAAS.

Kolaviron attenuates diclofenac-induced nephrotoxicity in male Wistar rats.

The beneficial effects of kolaviron, a natural biflavonoid from the seeds of Garcinia kola, have been attributed to its antioxidant and anti-inflammatory activities. This study was designed to investigate the renoprotective effect of kolaviron in rat model of diclofenac (DFC)-induced acute renal failure. Thirty-five male Wistar rats were divided into 7 groups of 5 rats each as follows: a control group that received propylene glycol orally and treatment groups that received DFC, DFC recovery, DFC followed by kolaviron at 3 different doses, and kolaviron only. DFC-treated rats showed sluggishness, illness, and anorexia. Their urine contained appreciable protein, glucose, and ketone bodies. Histopathological examination of their kidneys revealed profound acute tubular necrosis. DFC treatment significantly increased levels of plasma creatinine, urea, sodium, chloride, potassium ions, and increased renal tissue activities of superoxide dismutase, catalase, levels of malondialdehyde, and hydrogen peroxide. Fractional excretion of sodium and potassium and renal tissue levels of reduced glutathione and prostaglandin E2 (PGE2) decreased significantly in DFC-treated groups. However, kolaviron administration significantly reduced the toxic effect of DFC on PGE2 release; plasma levels of creatinine, urea, glucose, and electrolytes; and significantly attenuated renal tubular and oxidative damages. Furthermore, the effects of DFC administration on food consumption, water intake, urine output and urine protein, glucose, ketone bodies, and electrolytes were significantly attenuated in animals treated with kolaviron. The results suggested that kolaviron ameliorated DFC-induced kidney injury in Wistar rats by decreasing renal oxidative damage and restoration of renal PGE2 release back to the basal levels.

Diclofenac-induced biochemical changes in nephrotoxicity among male Albino rats

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with adverse renal effects caused by the reduction in synthesis of renal prostaglandins in sensitive persons or animal species, and potentially during long-term use in non-sensitive persons if resistance to side effects decreases with age. The effects of diclofenac sodium on the kidneys were studied during 4 1/2 hours in eight patients with normal renal function. Urinary output decreased within 10 min after the injection, and maximally by 80%. The renal plasma flow and the glomerular filtration rate initially diminished significantly, by 35%, but began to increase after only 2 hours. The dominant and persistent effect was a reduction of free water clearance, with maximum fall from 5.9 to 0.08ml/min after 2 1/2 hours. Aim: The aim of this study was to evaluate the effects of diclofenac-induced acute nephrotoxicity using biochemical parameters in rats.Methods: 12 male Wistar rats allotted in 4 equal groups were intraperitoneally injected with 0, 10, 50 and 100mg/kg diclofenac, respectively and 12 hours after injection, blood serum samples were collected for assessment of basic renal function test parameters such as urea, creatinine, and uric acid, sodium, Potassium.Results: Rats treated up to 50mg/kg diclofenac were considered to be within normal range in rats. By increase in dose more than 50mg/kg showed significant increases in uremia were evidenced in intoxicated animals. Observed specifically in group IV Rats.Conclusions: In this study, uremia, as an indicator of kidney damage, was significantly increased depending on dose. Diclofenac may cause kidney damage depending on dose and this effect may also be observed. NSAIDs-induced nephrotoxicity may be due to the inhibitory effect of these drugs on prostaglandin synthesis, thus causing kidney ischemia.