ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-PO286

Antifibrotic Effects of Tadalafil, a Phosphodiesterase 5 Inhibitor, with PAI1 Downregulation via cGMP in Rats and Fibroblasts

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Noda, Misuzu, Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
  • Hotta, Yuji, Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
  • Naiki-Ito, Aya, Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
  • Tomita, Natsumi, Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
  • Sanagawa, Akimasa, Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
  • Kataoka, Tomoya, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Japan
  • Hibi, Yoko, Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
  • Takahashi, Satoru, Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
  • Kimura, Kazunori, Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
Background

Renal fibrosis is common in cases of renal dysfunction, and the development of therapeutic agents for renal fibrosis is desired. It was recently reported that phosphodiesterase 5 (PDE5) inhibitors, used for the management of erectile dysfunction and pulmonary hypertension due to increased cGMP, have renoprotective effects. Thus, in this study, we investigated whether tadalafil, a PDE5 inhibitor, has antifibrotic effects via cGMP in rats and renal fibroblasts.

Methods

Dahl salt-sensitive rats were used as a renal dysfunction model and divided into the following groups: normal salt (NS), high salt (HS), and HS plus tadalafil (HS+T). The NS group was fed a normal diet (0.3% NaCl), and the HS group and HS+T group were fed a high-salt diet (8% NaCl). Tadalafil (10 mg/kg/day) was orally given once a day. After 8 weeks, renal fibrosis was evaluated using AZAN staining. The mRNA expression level of the profibrotic factor, plasminogen activator inhibitor1 (PAI1), was also examined. Furthermore, NRK-49F cells, fibroblasts, were treated with the vehicle, transforming growth factor (TGF)β1 (2 ng/ml), or TGFβ1 + 8-Br-cGMP (1 mM). After 6 h, PAI1 mRNA expression levels and active PAI1 protein levels were measured.

Results

Collagen-rich areas visualized by AZAN-staining obviously increased in the HS group compared with that in the NS group and those areas decreased in the HS+T group compared with that in the HS group. Furthermore, while PAI1 mRNA expression in kidney tissue significantly increased in the HS group compared with that in the NS group (P < 0.01), it decreased in the HS+T group compared with that in the HS group (P = 0.06). The expression levels of PAI1 mRNA in TGFβ1-stimulated NRK-49F cells increased compared with those in the vehicle-treated cells. 8-Br-cGMP addition decreased the expression levels of PAI1 mRNA. Active PAI1 protein levels in the TGFβ1-stimulated cells was significantly upregulated compared with that of the vehicle-treated cells (P < 0.01) and that of the 8-Br-cGMP-treated cells was significantly downregulated compared with that of the TGFβ1-stimulated cells (P < 0.01).

Conclusion

Tadalafil shows antifibrotic effects, which may be due to the prevention of active PAI1 expression due to increased cGMP in fibroblasts.