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Effect of a novel phosphodiesterase 5 inhibitor, CPD1, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury

LIU Ao-Lu¹, LI Zhuang¹, LU Mei-Zhi², QIU Hao-Heng¹, XIE Zhong-Lian¹, LIU Xiao-Qing¹, ZHAO Allan Zi-Jian¹, MU Yun-Ping^1,*, LI Fang-Hong¹

¹The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China；²Huadu District People’s Hospital of Guangzhou, Guangzhou 510800, China

Abstract

This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose- dependently inhibited the expression of ECM-related proteins induced by transforming growth factor β1 (TGF-β1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-β signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.

Key words: phosphodiesterase 5 inhibitors; CPD1; renal ischemia-reperfusion injury; renal interstitial fibrosis; TGF-β signaling pathway

Received: 　　Accepted:

Corresponding author: 穆云萍　　E-mail:

DOI: 10.13294/j.aps.2022.0103

Citing This Article：

LIU Ao-Lu, LI Zhuang, LU Mei-Zhi, QIU Hao-Heng, XIE Zhong-Lian, LIU Xiao-Qing, ZHAO Allan Zi-Jian, MU Yun-Ping, LI Fang-Hong. Effect of a novel phosphodiesterase 5 inhibitor, CPD1, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury. Acta Physiol Sin 2023; 75 (1): 1-9 (in Chinese with English abstract).