A Newly Synthesized Specific PDE5a Inhibitor LW1646 Attenuated Lipid-Induced Kidney Injuries through Inhibiting Endoplasmic Reticulum Stress.

Hyperlipidemia plays an important role in the progression of kidney injury, likely due to renal lipotoxicity. The purpose of the present study was to investigate whether a phosphodiesterase 5a (PDE5a) inhibitor prevented lipid-induced injury through inhibiting endoplasmic reticulum (ER) stress and apoptosis in the kidney. In human proximal tubule HK2 cells, saturated fatty acid palmitic acid (PA) treatment for 24h markedly increased protein abundance of ER stress makers BiP and CHOP, which was associated with upregulated cleaved-caspase 3 expression and decreased ratio of Bcl2/Bax, two markers of apoptosis. A newly synthesized, specific PDE5 inhibitor LW1646 significantly decreased protein abundance of BiP, CHOP and cleaved-caspase 3, and increased the ratio of Bcl2/Bax in HK2 cells treated by PA, likely through increasing intracellular cGMP levels. LW1646 or sildenafil, a classical inhibitor of PDE5, attenuated PA-induced upregulation of inositol 1,4,5-triphate receptor (IP3R) mediating calcium efflux from ER to cytoplasm, prevented PA-induced mitochondrial depolarization, and promoted mitochondrial biogenesis in HK2 cells. Atrial natriuretic peptide (ANP) known to increase cGMP and to stimulate cGMP-PKG signaling pathway was used to further investigate a role of cGMP in protection of PA-induced cell injuries. ANP treatment suppressed PA-induced ER stress, apoptosis and intracellular calcium oscillation in HK2 cells. Co-treatment with ANP and LBQ657, a neprilysin inhibitor preventing hydrolysis of ANP, showed better protective effects than ANP treatment alone in HK2 cells treated with PA. Exogenous 8-Br-cGMP also attenuated PA-induced ER stress and apoptosis. KT-5823, a selective cGMP-dependent PKG inhibitor, blocked protection of ANP or cGMP in HK2 cells treated with PA. Compared with controls, in mice fed with high-fat diet for 8 weeks, the protein expression of BiP and CHOP in the kidney cortex showed 3-fold and 2-fold increases, respectively, which was prevented by LW1646 or sildenafil treatment. Interestingly, after high-fat diet for 8 weeks, PDE5 knockout mice showed attenuated ER stress and apoptosis in the kidney cortex compared with wildtype mice. In conclusion, PDE5a inhibitor LW1646 inhibited lipid-induced ER stress and apoptosis in renal tubular cells, likely via activating the cGMP-PKG signaling pathway and maintaining mitochondrial function, it may have a therapeutic potential for preventing lipid-induced kidney injury.