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.