Phosphodiesterase 1A overexpression contributes to the progression of renal fibrosis.

Abstract

Renal fibrosis is a common histological feature of chronic kidney disease. The role of phosphodiesterase 1A (PDE1A), a crucial molecule regulating cyclic guanosine monophosphate (cGMP) signaling in tubular epithelial cells, in renal fibrosis is unknown. We found that the mRNA of PDE1A was elevated in the urinary exosomes from patients with rapidly progressing IgA nephropathy. The PDE1A protein in renal tubular epithelial cells increased as renal function decline in patients with IgA nephropathy or diabetic kidney disease. In mouse models of unilateral ureter obstruction (UUO) and chronic folic acid nephropathy (FAN), renal interstitial fibrosis was significantly alleviated in tubular epithelial cell-specific Pde1a knockout (Pde1a-cKO) mice, or after treatment with ITI-214, a PDE1 inhibitor. In HK-2 cells, transforming growth factor β1 (TGF-β1) incubation induced PDE1A expression, which was prevented by pretreatment with ITI-214 or Pde1a siRNA. Overexpression of PDE1A exacerbated TGF-β1-induced matrix protein production. Inhibition of PDE1A reversed the TGF-β1-induced decrease in cGMP levels and protein kinase G (PKG) signaling, without affecting cyclic adenosine monophosphate (cAMP) levels. We demonstrated that PKG directly interacts with Thr41 of β-catenin, leading to an increase in phosphorylated β-catenin (Ser33/37/Thr41). PKG activation and inactivation of β-catenin were verified in UUO and FAN model in Pde1a-cKO mice or ITI-214-treated mice. Furthermore, vericiguat, a soluble guanylate cyclase (sGC) agonist, induced cGMP signaling and mitigated renal fibrosis in UUO mice. These findings suggest that PDE1A may play a key role in renal fibrosis. Both PDE1A inhibition or gene knockout, and sGC activation can prevent the progression of renal fibrosis.