Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation and lower urinary tract dysfunction in vivo

Abstract

Background Several studies show that prostatic fibrosis is associated with male lower urinary tract dysfunction (LUTD). Development of fibrosis is typically attributed to signaling through the transforming growth factor β (TGF‐β) pathway, but our laboratory has demonstrated that in vitro treatment of human prostatic fibroblasts with the C‐X‐C motif chemokine ligand 12 (CXCL12) chemokine stimulates myofibroblast phenoconversion and that CXCL12 has the capacity to activate profibrotic pathways in these cells in a TGF‐β‐independent manner. We have previously reported that feeding mice high‐fat diet (HFD) results in obesity, type II diabetes, increased prostatic fibrosis, and urinary voiding dysfunction. The purpose of this study was to test the hypothesis that in vivo blockade of the CXCL12/CXCR4 axis would inhibit the development of fibrosis‐mediated LUTD in HFD‐fed mice. Methods Two‐month‐old male senescence‐accelerated mouse prone‐6 mice were fed either a HFD or low‐fat diet (LFD) for 8 months. Half of each dietary group were given constant access to normal water or water that contained the C‐X‐C chemokine receptor type 4 (CXCR4; CXCL12 receptor) antagonist CXCR4AIII. At the conclusion of the study, mice were weighed, subjected to oral glucose tolerance testing and cystometry, and lower urinary tract tissues collected and assessed for collagen content. Results HFD‐fed mice became significantly obese, insulin resistant, and hyperglycemic, consistent with acquisition of metabolic syndrome, compared with LFD‐fed mice. Anesthetized cystometry demonstrated that HFD‐fed mice experienced significantly longer intercontractile intervals and greater functional bladder capacity than LFD‐fed mice. Immunohistochemistry demonstrated high levels of CXCR4 and CXCR7 staining in mouse prostate epithelial and stromal cells. Picrosirius red staining indicated significantly greater periurethral collagen deposition in the prostates of HFD than LFD‐fed mice. Treatment with the CXCR4 antagonist CXCR4AIII did not affect acquisition of metabolic syndrome but did reduce both urinary voiding dysfunction and periurethral prostate collagen accumulation. Conclusions This is the first study to report that obesity‐induced lower urinary tract fibrosis and voiding dysfunction can be repressed by antagonizing the activity of the CXCR4 chemokine receptor in vivo. These data suggest that targeting the CXCL12/CXCR4 signaling pathway may be a clinical option for the prevention or treatment of human male LUTD.

Prostate enlargement and altered urinary function are part of the aging process

“…In human prostate, an increase in collagen deposition and fibrosis has been identified as a contributing factor of urinary dysfunction [31]. In the mouse, previous studies have shown a significant increase in fibrosis and collagen deposition within the prostatic urethra in mice experiencing LUTD, suggesting that collagen changes can alter normal urination [17,32,33]. We calculated collagen deposition at the midpoint of the prostatic urethra and in the prostate lobes by quantifying birefringence of picrosirius red (PSR) staining under circular polarized light.…”

Inhibition of CXCR4 in Spinal Cord and DRG with AMD3100 Attenuates Colon-Bladder Cross-Organ Sensitization

“…15 The use of CXCR4 inhibitors can improve voiding dysfunction caused by bladder inflammation and obesity. 15,32 CXCR4 is an important modulator of nociception and pain sensitivity beyond its involvement in inflammation. Studies on rodents have shown that CXCR4 is expressed in DRG and spinal cord.…”

“… 15 The use of CXCR4 inhibitors can improve voiding dysfunction caused by bladder inflammation and obesity. 15 , 32 …”

Treatment of Stress Urinary Incontinence with Muscle Stem Cells and Stem Cell Components: Chances, Challenges and Future Prospects

“…For instance, studies using recombinant CXCL12 injections have shown positive effects on tissue regeneration [ 125 , 126 ]. However, there are published studies that seem to contradict these results and dispute the beneficial effects of CXCL12 on urological tissues [ 127 , 128 ]. Nevertheless, these studies focused on the secretion of physiologic CXCL12 that Ray et al showed to form dimers in physiologic conditions.…”