3 years ago

PKA/CREB signaling prevents adriamycin-induced podocyte apoptosis via upregulation of mitochondrial respiratory chain complexes.

Renhua Lu, Ayijiaken Kasimumali, Peng Xiang, Leyi Gu, Xiaohuan Chen, Huihua Pang, Shan Mou, Qin Wang, Kewei Xie, Zhaohui Ni, Mingli Zhu
Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Herein, we show that the pKA-agonist pCPT-cAMP prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNAi. The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1-a). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-a and ND3 promoters, suggesting that these promoters are CREB targets. In vivo, both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

Publisher URL: http://doi.org/10.1128/MCB.00181-17

DOI: 10.1128/MCB.00181-17

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