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

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.

 

Comments：

PDE-4 inhibitors, rolipram and roflumilast, improved kidney function in a doxorubicin-induced nephrotic syndrome model by preserving glomerular filtration barrier function, reducing inflammation, renal cell apoptosis and fibrosis, and decreasing serum protein and albumin loss, but only roflumilast reduced glomerular and tubular lesions in late-stage treatment.

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S1430	Rolipram	The PDE4 selective inhibitor, Rolipram, inhibited immunopurified PDE4B and PDE4D activities similarly, with IC50 values of approx. 130 nM and 240 nM respectively; an anti-inflammatory agent.

Related Targets

PDE