scholarly journals Collecting duct PGE2 responses reduce water loss with empagliflozin in mice with type 2 diabetes mellitus

2021 ◽  
Vol 5 (1) ◽  
pp. 023-030
Author(s):  
Nasrallah R ◽  
Zimpelmann J ◽  
Cheff V ◽  
Thibodeau JF ◽  
Burns KD ◽  
...  
Keyword(s):  
Water Transport ◽  
Water Loss ◽  
Collecting Duct ◽  
Quantitative Polymerase Chain Reaction ◽  
Receptor Subtypes ◽  
Diabetic Mice ◽  
Water Reabsorption ◽  
Receptor System ◽  
Ep Receptor

Introduction: Sodium-glucose cotransporter 2 inhibitors such as empagliflozin (EMPA) protect against diabetic kidney disease. Prostaglandin E2 (PGE2) the main renal product of cyclooxygenase-2, inhibits vasopressin (AVP)-water reabsorption in the collecting duct (CD). The novelty of this study is that for the first time, we examined if EMPA affects the renal PGE2/EP receptor system and determined if CD responses to EMPA prevent water loss. Methods: Four groups of adult male mice were studied after 6 weeks of treatment: control (db/m), db/m+EMPA (10 mg/kg/day in chow), type 2 diabetic diabetic/dyslipidemia (db/db), and db/db+EMPA. Tubules were microdissected for quantitative polymerase chain reaction (qPCR) and CD water transport was measured in response to AVP, with or without PGE2. Results: Hyperglycemia and albuminuria were attenuated by EMPA. Renal mRNA expression for COX, PGE synthase, PGE2 (EP) receptor subtypes, CD AVP V2 receptors and aquaporin-2 was elevated in db/db mice, but unchanged by EMPA. Urine PGE2 levels increased in db/db but were unchanged by EMPA. AVP-water reabsorption was comparable in db/m and db/m+EMPA, and equally attenuated to 50% by PGE2. In db/db mice, AVP-water reabsorption was reduced by 50% compared to non-diabetic mice, and this reduction was unaffected by EMPA. In db/db mice, AVP-stimulated water transport was more significantly attenuated with PGE2 (62%), compared to non-diabetic mice, but this attenuation was reduced in response to EMPA, to 28%. Conclusion: In summary, expression of renal PGE2/EP receptors is increased in db/db mice, and this expression is unaffected by EMPA. However, in diabetic CD, PGE2 caused a greater attenuation in AVP-stimulated water reabsorption, and this attenuation is reduced by EMPA. This suggests that EMPA attenuates diabetes-induced excess CD water loss.

Functional and molecular aspects of prostaglandin E receptors in the cortical collecting duct

1995 ◽  
Vol 73 (2) ◽  
pp. 172-179 ◽  
Author(s):  
Richard L. Hébert ◽  
Richard M. Breyer ◽  
Harry R. Jacobson ◽  
Matthew D. Breyer
Keyword(s):  
In Situ Hybridization ◽  
Cyclic Amp ◽  
Water Transport ◽  
Collecting Duct ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Cortical Collecting Duct ◽  
Endogenous Prostaglandin ◽  
Ep Receptor

Endogenous prostaglandin (PG) E2 production potently modulates salt and water transport in the kidney. Multiple direct effects of PGE2 on epithelial water and sodium transport have been demonstrated in the rabbit cortical collecting duct (CCD). Both functional and molecular studies now suggest that these disparate effects of PGE2 on CCD function are mediated by different EP receptors. When added in the presence of vasopressin, PGE2 inhibits cyclic AMP generation and water absorption. These effects are mediated via an inhibitory G-protein (Gi). In situ hybridization demonstrates high levels of expression of the Gi-coupled EP3 receptor in the rabbit collecting duct. However, by itself, PGE2 also stimulates cyclic AMP generation and water permeability. These effects appear to be mediated via a distinct EP receptor (possibly an EP4 receptor). PGE2 also increases intracellular Ca2+ in the CCD and inhibits Na+ absorption via a Ca2+-dependent mechanism. The EP1 receptor is postulated to be responsible for this action of PGE2. We suggest receptor-selective prostaglandin analogs may be used to selectively modulate sodium and water transport in the kidney.Key words: EP receptor subtypes, G-proteins, in situ hybridization, prostaglandin E2, phosphatidylinositol biphosphate hydrolysis.

scholarly journals Renal prostaglandin E2 receptor (EP) expression profile is altered in streptozotocin and B6-Ins2Akita type I diabetic mice

2007 ◽  
Vol 292 (1) ◽  
pp. F278-F284 ◽  
Author(s):  
Rania Nasrallah ◽  
Huaqi Xiong ◽  
Richard L. Hébert
Keyword(s):  
Expression Profile ◽  
Receptor Expression ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Type I ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Urine Albumin ◽  
Ep Receptor ◽  
Prostaglandin E2 Receptor

The homeostatic function of prostaglandin E2 (PGE2) is dependent on a balance of EP receptor-mediated events. A disruption in this balance may contribute to the progression of renal injury. Although PGE2 excretion is elevated in diabetes, the expression of specific EP receptor subtypes has not been studied in the diabetic kidney. Therefore, the purpose of this study was to characterize the expression profile of four EP receptor subtypes (EP1-4) in 16-wk streptozotocin (STZ) and B6-Ins2Akita type I diabetic mice. In diabetic mice, the ratio of kidney weight to body weight was increased twofold compared with controls, blood glucose was elevated, but urine albumin was only increased in B6-Ins2Akita mice. The excretion of PGE2 and its metabolite was augmented two- to fourfold as determined by enzyme immunoassay. Accordingly, renal cyclooxygenases were also increased in diabetic mice, with isoform-specific and regional differences in each model. Finally, there was altered EP1-4 receptor expression in diabetic kidneys, with significant differences between STZ and B6-Ins2Akita mice (fold-control). In STZ mice, cortical EP1 increased by 1.6, EP3 increased by 2.3, and EP4 decreased by 0.63; yet in B6-Ins2Akita mice, cortical EP1 increased by 2.4, but there was a general decrease in the remaining subtypes. Similarly, in the STZ medulla EP3 increased by 3.6, but both EP1 and EP3 increased by 5.5 and 1.95, respectively, in B6-Ins2Akita mice. Therefore, knowing the pattern of change in relative EP receptor expression in the kidney could be useful in identifying specific EP targets for the prevention of various components of diabetic kidney disease.

Differential localization of prostaglandin E receptor subtypes in human kidney

1996 ◽  
Vol 270 (5) ◽  
pp. F912-F918 ◽  
Author(s):  
M. D. Breyer ◽  
L. Davis ◽  
H. R. Jacobson ◽  
R. M. Breyer
Keyword(s):  
In Situ Hybridization ◽  
Collecting Duct ◽  
Human Kidney ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Ep Receptors ◽  
Inner Medullary Collecting Duct ◽  
Ep Receptor ◽  
Medullary Collecting Duct

Four prostaglandin E2 (PGE2) receptors designated EP1, EP2, EP3, and EP4 have been pharmacologically identified, cloned, and sequenced. The present studies determined the intrarenal distribution of these EP-receptor subtypes in human kidney using in situ hybridization with riboprobes for the human EP receptors. mRNA for the phosphatidylinositol hydrolysis-coupled EP receptor was highly expressed in cortical, outer medullary, and inner medullary collecting duct. RNA for the Gi-coupled EP3 receptor was primarily expressed in the cortical and outer medullary collecting duct, as well as in the medullary thick ascending limb; however, it was absent from the inner medullary collecting duct. Expression of mRNA for EP1 and EP3 in connecting segment could not be excluded. There was no expression of the GS-coupled EP2 receptor mRNA detected in human kidney by in situ hybridization; however, mRNA for the GS-coupled EP4 receptor was highly expressed in the glomerulus. These studies demonstrate distinct regions of intrarenal expression for the different EP receptors and suggest that each receptor subtype may modulate different aspects of renal function in humans.

Urinary concentrating function in mice lacking EP3 receptors for prostaglandin E2

1998 ◽  
Vol 275 (6) ◽  
pp. F955-F961 ◽  
Author(s):  
Eric F. Fleming ◽  
Krairek Athirakul ◽  
Michael I. Oliverio ◽  
Mikelle Key ◽  
Jennifer Goulet ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Renal Medulla ◽  
Urine Osmolality ◽  
Receptor Subtypes ◽  
Cortical Collecting Duct ◽  
Prostanoid Production ◽  
Organ Systems ◽  
Ep Receptor ◽  
The Individual

The actions of prostaglandin (PG) E2 are mediated by four distinct classes of PGE2E-prostanoid (EP) receptors (EP1through EP4). However, the in vivo functions of the individual EP receptor subtypes have not been delineated. To study the functions of one of these subtypes, the EP3 receptor, we generated EP3-deficient (−/−) mice by gene targeting. EP3 −/− animals survived in expected numbers, reproduced, and had no obvious abnormalities in their major organ systems. Because the EP3 receptor is expressed at high levels in the renal medulla and cortical collecting duct, and because previous studies have suggested that the EP3 receptor might antagonize the effects of vasopressin in the distal nephron, we examined urinary concentrating functions in EP3−/− mice. Basal urine osmolality (UOsm) was similar in groups of EP3 −/− and wild-type (EP3 +/+) mice. However, after inhibition of endogenous PGE2 production by indomethacin, UOsm increased significantly in EP3 +/+ but not in EP3 −/− mice. Despite this insensitivity to acute inhibition of prostanoid production, EP3 −/− mice concentrated and diluted their urine normally in response to a series of physiological stimuli. This suggests that PGE2 acts through the EP3 receptor to modulate urinary concentrating mechanisms in the kidney, but these effects are not essential for normal regulation of urinary osmolality.

1172-P: GLUT4-Overexpressing Engineered Muscle Tissue Implants as a Potential Novel Therapy for Type 2 Diabetes: Lessons from Diabetic Mice

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1172-P
Author(s):  
MARGARITA BECKERMAN ◽  
EDDY KARNIELI ◽  
CHAVA HAREL ◽  
AMIRA KLIP ◽  
PHILIP J. BILAN ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Muscle Tissue ◽  
Diabetic Mice ◽  
Novel Therapy

scholarly journals Crocodile blood supplementation protects vascular function in diabetic mice

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chui Yiu Bamboo Chook ◽  
Francis M. Chen ◽  
Gary Tse ◽  
Fung Ping Leung ◽  
Wing Tak Wong
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Quantitative Polymerase Chain Reaction ◽  
Functional Study ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Gene Expressions ◽  
Inflammatory State ◽  
Crocodile Blood

Abstract Cardiovascular disease is a major cause of mortality in diabetic patients due to the heightened oxidative stress and pro-inflammatory state in vascular tissues. Effective approaches targeting cardiovascular health for diabetic patients are urgently needed. Crocodile blood, an emerging dietary supplement, was suggested to have anti-oxidative and anti-inflammatory effects in vitro, which have yet to be proven in animal models. This study thereby aimed to evaluate whether crocodile blood can protect vascular function in diabetic mice against oxidation and inflammation. Diabetic db/db mice and their counterparts db/m+ mice were treated daily with crocodile blood soluble fraction (CBSF) or vehicle via oral gavage for 4 weeks before their aortae were harvested for endothelium-dependent relaxation (EDR) quantification using wire myograph, which is a well-established functional study for vascular function indication. Organ culture experiments culturing mouse aortae from C57BL/6 J mice with or without IL-1β and CBSF were done to evaluate the direct effect of CBSF on endothelial function. Reactive oxygen species (ROS) levels in mouse aortae were assessed by dihydroethidium (DHE) staining with inflammatory markers in endothelial cells quantified by quantitative polymerase chain reaction (qPCR). CBSF significantly improved deteriorated EDR in db/db diabetic mice through both diet supplementation and direct culture, with suppression of ROS level in mouse aortae. CBSF also maintained EDR and reduced ROS levels in mouse aortae against the presence of pro-inflammatory IL-1β. Under the pro-inflammatory state induced by IL-1β, gene expressions of inflammatory cytokines were downregulated, while the protective transcripts UCP2 and SIRT6 were upregulated in endothelial cells. Our study suggests a novel beneficial effect of crocodile blood on vascular function in diabetic mice and that supplementation of diet with crocodile blood may act as a complementary approach to protect against vascular diseases through anti-oxidation and anti-inflammation in diabetic patients. Graphical abstract

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