Genetic Deletion of Phosphodiesterase 4D in the Liver Improves Kidney Damage in High-fat Fed Mice: Liver-kidney Crosstalk

A growing body of epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for chronic kidney disease (CKD), but the regulatory mechanism linking NAFLD and CKD remains unclear. Our previous studies have shown that overexpression of PDE4D in mouse liver is sufficient for NAFLD, but little is known about its role in kidney injury. Here, liver-specific PDE4D conditional knockout (LKO) mice, adeno-associated virus 8 (AAV8)-mediated gene transfer of PDE4D and the PDE4 inhibitor roflumilast were used to assess the involvement of hepatic PDE4D in NAFLD-associated renal injury. We found that mice fed a high-fat diet (HFD) for 16 weeks developed hepatic steatosis and kidney injury, with an associated increase in hepatic PDE4D but no changes in renal PDE4D. Furthermore, liver-specific knockout of PDE4D or pharmacological inhibition of PDE4 with roflumilast ameliorated hepatic steatosis and kidney injury in HFD-fed diabetic mice. Correspondingly, overexpression of hepatic PDE4D resulted in significant renal damage. Mechanistically, highly expressed PDE4D in fatty liver promoted the production and secretion of TGF-β1 into blood, which triggered kidney injury by activating SMADs and subsequent collagen deposition. Our findings revealed PDE4D might act as a critical mediator between NAFLD and associated kidney injury and indicated PDE4 inhibitor roflumilast as a potential therapeutic strategy for NAFLD-associated CKD.