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      Elucidation of cGMP-dependent induction of mitochondrial biogenesis through PKG and p38 MAPK in the kidney

      1 , 1 , 1 , 2

      American Journal of Physiology-Renal Physiology

      American Physiological Society

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          Abstract

          Previous studies have shown that cGMP increases mitochondrial biogenesis (MB). Our laboratory has determined that formoterol and LY344864, agonists of the β 2-adrenergic receptor and 5-HT 1F receptor, respectively, signal MB in a soluble guanylyl cyclase (sGC)-dependent manner. However, the pathway between cGMP and MB produced by these pharmacological agents in renal proximal tubule cells (RPTCs) and the kidney has not been determined. In the present study, we showed that treatment of RPTCs with formoterol, LY344864, or riociguat, a sGC stimulator, induces MB through protein kinase G (PKG), a target of cGMP, and p38, an associated downstream target of PKG and a regulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in RPTCs. We also examined if p38 plays a role in PGC-1α phosphorylation in vivo. Administration of l-skepinone, a potent and specific inhibitor of p38α and p38β, to naïve mice inhibited phosphorylated PGC-1α localization in the nuclear fraction of the renal cortex. Taken together, we demonstrated a pathway, sGC/cGMP/PKG/p38/PGC-1α, for pharmacological induction of MB and the importance of p38 in this pathway.

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          Author and article information

          Journal
          American Journal of Physiology-Renal Physiology
          American Journal of Physiology-Renal Physiology
          American Physiological Society
          1931-857X
          1522-1466
          February 01 2020
          February 01 2020
          : 318
          : 2
          : F322-F328
          Affiliations
          [1 ]Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona
          [2 ]Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona
          Article
          10.1152/ajprenal.00533.2019
          7052650
          31841384
          © 2020

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