Ursodeoxycholic acid ameliorates erectile dysfunction and corporal fibrosis in diabetic rats by inhibiting the TGF-β1/Smad2 pathway.

Abstract

Corporal tissue fibrosis is critical in diabetes-associated erectile dysfunction. Transforming growth factor-β1/Small mothers against decapentaplegic-2 (TGF-β1/Smad2) contributes to the induction of fibrosis in corporal tissue. Smad7 is accepted as a general negative regulator of Smad signaling, although its role in corporal fibrosis is unknown. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid used for biliary and liver related disorders and has antifibrotic effects in the liver. This study investigated the effects of UDCA on diabetic erectile dysfunction. Forty-eight male Spraque Dawley rats were divided into six groups: nondiabetic (n = 6), nondiabetic+20 mg/kg UDCA (n = 6), nondiabetic+80 mg/kg UDCA (n = 6), diabetic (n = 10), diabetic+20 mg/kg UDCA (n = 10), diabetic+80 mg/kg UDCA (n = 10). Diabetes was induced by intraperitoneal injection of 60 mg/kg Streptozocin. UDCA (20 and 80 mg/kg/day) or saline was subsequently administered via oral gavage for 56 days. Erectile function was evaluated as measurement of maximum intracavernosal pressure (m-ICP)/mean arterial pressure (MAP) and total ICP/MAP. Corporal tissues were evaluated by Western blotting and Masson's trichrome staining. Electrical stimulation-induced m-ICP/MAP responses were higher in UDCA-treated diabetic rats compared to untreated diabetic rats, respectively (20 mg/kg; 4 V: 0.77 ± 0.11 vs 0.45 ± 0.09, p = 0.0001 and 80 mg/kg; 4 V: 0.78 ± 0.11 vs 0.45 ± 0.09, p = 0.0001) UDCA prevented the increase in phospho-Smad2 and fibronectin protein expressions in diabetic corporal tissue both at 20 mg/kg (p = 0.0002, p = 0.002 respectively) and 80 mg/kg doses (p < 0.0001 for both). Smad7 protein expressions were significantly increased in the UDCA-treated diabetic groups compared to the untreated diabetic group (20 mg/kg: p = 0.0079; 80 mg/kg: p = 0.004). Furthermore, UDCA significantly prevented diabetes-induced increase in collagen (20 mg/kg: p = 0.0172; 80 mg/kg: p = 0.0003) and smooth muscle loss (20 mg/kg: p = 0.044; 80 mg/kg: p = 0.039). In conclusion, UDCA has a potential protective effect on erectile function in diabetic rats by altering fibrotic pathways via inhibition of TGF-β1/Smad2 and activation of Smad7.