Therapeutic treatment with phosphodiesterase-4 inhibitors alleviates kidney injury and renal fibrosis by increasing MMP-9 in a doxorubicin-induced nephrotoxicity mouse model

[Display omitted] •Therapeutic treatment with PDE4 inhibitor ameliorates renal function associated to doxorubicin-induced nephropathy.•Therapeutic treatment with PDE4 inhibitors reverses established inflammation associated to doxorubicin-induced nephropathy.•PDE4 inhibitor induces MMP9 activation and reduces established renal fibrosis.•Roflumilast may be a promising new treatment for the clinical management of nephropathy. Nephrotic syndrome (NS) is associated with kidney dysfunction and is an important cause of morbidity and mortality in industrialized countries. Here, we evaluated the effects of the phosphodiesterase-4 (PDE-4) inhibitors rolipram and roflumilast on a doxorubicin-induced NS model. Early-stage rolipram treatment preserved glomerular filtration barrier function, as indicated by reduced serum protein and albumin loss and the prevention of hypercholesterolemia. These effects were associated with reduced glomerular and tubular lesions and abrogated renal cell apoptosis. In addition, rolipram treatment reduced inflammation, which was characterized by a decrease in macrophage accumulation and reduced levels of CCL2 and TNF in the kidneys. Rolipram also reduced renal fibrosis, which was associated with decreased α-smooth muscle actin (α-SMA) area and increased metalloproteinase 9 (MMP9) activity in renal tissue. Late-stage rolipram or roflumilast treatment preserved glomerular filtration barrier function, as characterized by reduced serum albumin loss, decreased proteinuria, and the prevention of hypercholesterolemia. Importantly, only roflumilast treatment was associated with a reduction in glomerular and tubular lesions at this time point. In addition, both rolipram and roflumilast reduced renal tissue fibrosis and MMP9 activity in renal tissue.