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.