Insight into SLC9A3 deficiency-mediated micturition dysfunction caused by electrolyte imbalance

• Published in: Biomedicine & pharmacotherapy 2023-02, Vol.158, p.114155-114155, Article 114155
• Main Authors: Chen, Kuo-Chiang, Chang, Meng-Lin, Lin, Chun-Sian, Rajneesh, Chellappan Praveen, Liao, Chun-Hou, You, Wen-Chen, Maa, Hung-Chune, Wu, Yi-No
• Format: Article
• Language: English
• Subjects: Animals; Bladder dysfunction; Detrusor muscle atrophy; Electrolyte imbalance; Electrolytes; Humans; Mice; SLC9A3; Sodium-Hydrogen Exchangers; Urinary Bladder - pathology; Urination
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.114155

Solute carrier family nine isoform 3 (SLC9A3) is an Na+/H+ exchanger that regulates Ca2+ homeostasis. SLC9A3 is largely involved in the transepithelial absorption of Na+/H+ and frequently functions in pair with a Cl−/HCO3− exchanger. To investigate the impact and pathophysiological mechanisms of long-term SLC9A3 deficiency on lower urinary tract symptoms (LUTS) in a mouse model Slc9a3 knockout and wild-type mice (average >6 months) were used. The effects of SLC9A3 depletion on bladder and urethral functions and effectiveness of voiding were assessed using a cystometrogram (CMG). Histology, blood electrolytes, and gene expression were also analyzed. The SLC9A3-deficient mice had smaller gross bladders than the wild-type mice. The CMG analysis revealed normal peak micturition pressure, higher threshold pressure, short intercontraction interval, less voided volume, and poor compliance in the SLC9A3-deficient mice, similar to clinical LUTS. Histological analysis revealed loose detrusor muscle and loss of transformability of the urothelium in the SLC9A3-deficient mice. Masson's trichrome analysis revealed severe collagen deposition in the detrusor muscle. Immunofluorescence staining also demonstrated a significant decrease in cytokeratins 5 and 20. Gene and protein expression analyses confirmed that SLC9A3 does not act directly on bladder tissue. Homeostasis was correlated with bladder dysfunction in the SLC9A3-deficient mice. Fibrosis and collagen deposition in the bladder of the SLC9A3-deficient mice is due to bladder inflammation because of decreased blood flow and deregulated systemic homeostasis. Long-term SLC9A3 depletion causes progressive bladder dysfunction, similar to human LUTS. Electrolyte imbalance causes SLC9A3 deficiency-mediated progressive micturition dysfunction. [Display omitted] •Slc9a3−/− mice were confirmed to frequently urinate.•Slc9a3−/− mice demonstrated collagen deposition and bladder fibrosis.•Expression studies confirmed that SLC9A3 expression was high in renal tissues.•Histological findings identified bladder barrier loss and urothelium damage.•Electrolyte dysregulation causes homeostatic problems and LUTS.