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

Kuo-Chiang Chen; Meng-Lin Chang; Chun-Sian Lin; Chellappan Praveen Rajneesh; Chun-Hou Liao; Wen-Chen You; Hung-Chune Maa; Yi-No Wu

doi:10.1016/j.biopha.2022.114155

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

Biomed Pharmacother. 2023 Feb:158:114155. doi: 10.1016/j.biopha.2022.114155. Epub 2023 Jan 3.

Authors

Kuo-Chiang Chen¹, Meng-Lin Chang², Chun-Sian Lin³, Chellappan Praveen Rajneesh⁴, Chun-Hou Liao⁵, Wen-Chen You⁴, Hung-Chune Maa⁶, Yi-No Wu⁷

Affiliations

¹ School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Department of Urology, Cathay General Hospital, Taipei City 106438, Taiwan.
² School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Department of Urology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 243089, Taiwan.
³ Graduate Institute of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan.
⁴ School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan.
⁵ School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei City 231403, Taiwan.
⁶ School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Department of Pathology, Cardinal Tien Hospital, New Taipei City 231403, Taiwan. Electronic address: a1959480613@gmail.com.
⁷ School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan. Electronic address: 133838@mail.fju.edu.tw.

PMID: 36916397
DOI: 10.1016/j.biopha.2022.114155

Abstract

Background: 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.

Objective: To investigate the impact and pathophysiological mechanisms of long-term SLC9A3 deficiency on lower urinary tract symptoms (LUTS) in a mouse model MATERIALS AND METHODS: 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.

Results: 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.

Discussion: 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.

Conclusion: Electrolyte imbalance causes SLC9A3 deficiency-mediated progressive micturition dysfunction.

Keywords: Bladder dysfunction; Detrusor muscle atrophy; Electrolyte imbalance; SLC9A3.

MeSH terms

Animals
Electrolytes
Humans
Mice
Sodium-Hydrogen Exchangers
Urinary Bladder* / pathology
Urination*

Substances

Electrolytes
Sodium-Hydrogen Exchangers
Slc9a3 protein, mouse