Female Type 1 Diabetic Akita Mice Demonstrate Increased Bladder Contractility via FP Receptor Activation due to NLRP3-Mediated Inflammation.

Publisher: IMR Press Country of Publication: Singapore NLM ID: 101612996 Publication Model: Print Cited Medium: Internet ISSN: 2768-6698 (Electronic) Linking ISSN: 27686698 NLM ISO Abbreviation: Front Biosci (Landmark Ed) Subsets: MEDLINE

Publication: 2022- : Singapore : IMR Press
Original Publication: Searington, NY : Frontiers in Bioscience

NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein*/genetics ; Urinary Bladder*/metabolism ; Urinary Bladder*/physiopathology ; Receptors, Prostaglandin*/metabolism ; Receptors, Prostaglandin*/genetics ; Muscle Contraction* ; Diabetes Mellitus, Type 1*/physiopathology ; Diabetes Mellitus, Type 1*/metabolism ; Mice, Knockout*; Animals ; Female ; Mice ; Inflammation/metabolism ; Inflammation/physiopathology ; Mice, Inbred C57BL ; Diabetes Mellitus, Experimental/physiopathology ; Diabetes Mellitus, Experimental/metabolism

Background: Diabetic bladder dysfunction (DBD) is driven in part by inflammation which dysregulates prostaglandin release in the bladder. Precise inflammatory mechanisms responsible for such dysregulation have been elusive. Since prostaglandins impact bladder contractility, elucidating these mechanisms may yield potential therapeutic targets for DBD. In female Type 1 diabetic Akita mice, inflammation mediated by the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome is responsible for DBD. Here, we utilized female Akita mice crossbred with NLRP3 knock-out mice to determine how NLRP3-driven inflammation impacts prostaglandin release within the bladder and prostaglandin-mediated bladder contractions.
Methods: Akita mice were crossbred with NLRP3-⁣/- mice to yield four groups of non-diabetics and diabetics with and without the NLRP3 gene. Females were aged to 30 weeks when Akitas typically exhibit DBD. Urothelia and detrusors were stretched ex vivo to release prostaglandins. Prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) were quantified using enzyme linked immunosorbent assays (ELISA). In separate samples, ex vivo contractile force to PGE2 and PGF2α +/- the prostaglandin F (FP) receptor antagonist, AL8810, was measured. FP receptor protein expression was determined via western blotting.
Results: Stretch-induced PGE2 release increases in urothelia but decreases in detrusors of diabetics. However, PGE2-mediated bladder contractions are not impacted. Conversely, diabetics show no changes in PGF2α release, but PGF2α-mediated contractions increase significantly. This is likely due to signaling through the FP receptors as FP receptor antagonism prevents this increase and diabetics demonstrate a four-fold increase in FP receptor proteins. Without NLRP3-mediated inflammation, changes in prostaglandin release, contractility, and receptor expression do not occur.
Conclusion: NLRP3-dependent inflammation dysregulates prostaglandin release and prostaglandin-mediated bladder contractions in diabetic female Akita mice via FP receptor upregulation.
Competing Interests: The authors declare no conflict of interest.
(© 2024 The Author(s). Published by IMR Press.)

K12 DK100024 United States DK NIDDK NIH HHS

Keywords: Akita; FP receptor; NLRP3; Type 1 diabetes; diabetic bladder dysfunction; inflammation; myograph; prostaglandin

0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (Receptors, Prostaglandin)
0 (Nlrp3 protein, mouse)
0 (prostaglandin F2alpha receptor)

Date Created: 20240429 Date Completed: 20240429 Latest Revision: 20240509

20240509

10.31083/j.fbl2904154

38682210