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Sources of Funding: A Stanford institutional grant, SPARK, was awarded for completing this research

Introduction

Interstitial cystitis (IC) is a chronic disease, characterized by varying degrees of painful and frequent urination, which likely occurs due to a variety of etiologic factors acting through multiple pathogenic mechanisms. Although this chronic and painful condition affects up to 1% of women, there are few effective treatments. One hypothesized pathophysiologic mechanism involves thinning and dysfunction of the bladder endothelium and glycosaminoglycan (GAG) layer, leading to altered bladder epithelial permeability, migration of urinary solutes into the bladder interstitium and ultimately bladder pain and reduced bladder capacity. Pioglitazone has been shown in previous murine studies to increase bladder mucosal cell proliferation when given systemically. For patients with IC, where decreased mucosal cell proliferation is a likely etiologic factor in the disease process, this effect may prove therapeutic.

Methods

Using a previously described animal model for IC, 6-week-old female Sprague-Dawley rats were treated with biweekly cyclophosphamide injections (35mg/kg) to induce cystitis. Animals were divided into 4 groups (n=6): IC plus daily sham saline gavage (IC), IC plus daily pioglitazone gavage (150mg/kg) (IC+P), normal rats with daily pioglitazone (PIO), and normal rats with neither IC nor pioglitazone (CTRL). At the end of four weeks, urinary frequency was measured via counting spots on filter paper, and bladder capacity was measured cystometrically. Histologic examination was also performed, after embedding the excised bladders in paraffin, staining with haematoxylin and eosin (H&E), PAS and with Mason’s trichrome stain. Slides were reviewed in a blinded fashion by a pathologist for inflammation, bladder wall thickness, collagen deposition, and local tissue structure.

Results

On voiding paper tests, average voids per hour were: IC rats 10 +/- 2.44 , IC+P 4 +/-1.87, PIO 6 +/- 1.41, and CTRL voided 6 times/hour+/- 1.52. Comparison between IC and IC+P groups using students T-test showed a significant difference in voids/hour (P<.01). On cytometry, bladder volumes were significantly higher in IC+P versus IC (0.945 +/-0.122 ml vs 0.588 +/-0.165 ml s., P=.01) Control capacities averaged 0.82 +/- 0.20 ml and PIO capacities were similar at 0.94 +/-0.19ml. On histology, a diminished glycosaminoglycan layer was appreciated on cystitis bladders, and this effect was mitigated, though not resolved, in the treatment group.

Conclusions

Pioglitazone improved bladder function in rats with cyclophosphamide-induced cystitis with respect to both observed urinary frequency and measured cystometric capacity. Pioglitazone and other PPAR-gamma agonists, due to their propensity to cause bladder mucosal proliferation, may prove to be useful for treating interstitial cystitis, and deserve further study.

Funding

A Stanford institutional grant, SPARK, was awarded for completing this research