Elucidation of cGMP-Dependent Induction of Mitochondrial Biogenesis Through Protein Kinase G and p38 MAPK in the Kidney.

Previous studies have shown that cGMP increases mitochondrial biogenesis (MB). Our laboratory has determined that formoterol and LY344864, agonists of the b2-adrenergic and 5-HT1F receptor, respectively, signal MB in a sGC-dependent manner. However, the pathway between cGMP and MB produced by these pharmacological agents in renal proximal tubule cells (RPTC) and the kidney, has not been determined. We show that treatment of RPTC with formoterol, LY344864, or riociguat, an 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 PGC-1α expression in RPTC. We also examined if p38 plays a role in PGC-1α phosphorylation in vivo. L-Skepinone, a potent and specific inhibitor of p38α and p38β administration to naïve mice inhibited phosphorylated PGC-1α localization in the nuclear fraction of the renal cortex. Taken together, we have demonstrated a pathway, sGC/cGMP/PKG/p38/PGC-1α, for pharmacological induction of MB and the importance of p38 in this pathway.

[1]  R. Schnellmann,et al.  Identification of dual mechanisms mediating 5-hydroxytryptamine receptor 1F-induced mitochondrial biogenesis. , 2018, American journal of physiology. Renal physiology.

[2]  Y. Peterson,et al.  Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol , 2017, Scientific Reports.

[3]  J. Stasch,et al.  Renal effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence. , 2015, Current opinion in pharmacology.

[4]  Ami Patel,et al.  Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. , 2014, P & T : a peer-reviewed journal for formulary management.

[5]  S. Collins,et al.  A heart–adipose tissue connection in the regulation of energy metabolism , 2014, Nature Reviews Endocrinology.

[6]  R. Schnellmann,et al.  cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury , 2013, The Journal of Pharmacology and Experimental Therapeutics.

[7]  P. Seale,et al.  Brown and beige fat: development, function and therapeutic potential , 2013, Nature Medicine.

[8]  Shuxia Wang,et al.  Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function. , 2013, American journal of physiology. Renal physiology.

[9]  G. Ailhaud,et al.  Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. , 2012, The Journal of clinical investigation.

[10]  Wolfgang Albrecht,et al.  Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. , 2012, Nature chemical biology.

[11]  J. Auwerx,et al.  Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. , 2011, The American journal of clinical nutrition.

[12]  Xianglin Shi,et al.  Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3‐L1 adipocytes via the endothelial NO synthase‐cGMP‐protein kinase G signalling pathway , 2011, British journal of pharmacology.

[13]  V. Mitrović,et al.  Soluble Guanylate Cyclase Modulators in Heart Failure , 2011, Current heart failure reports.

[14]  J. Corbin,et al.  cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action , 2010, Pharmacological Reviews.

[15]  G. Shulman,et al.  Regulation of mitochondrial biogenesis. , 2010, Essays in biochemistry.

[16]  S. Herzig,et al.  Protein Kinase G Controls Brown Fat Cell Differentiation and Mitochondrial Biogenesis , 2009, Science Signaling.

[17]  G. Marsicano,et al.  Cannabinoid Type 1 Receptor Blockade Promotes Mitochondrial Biogenesis Through Endothelial Nitric Oxide Synthase Expression in White Adipocytes , 2008, Diabetes.

[18]  Kaushik Sengupta,et al.  Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. , 2008, Genes & development.

[19]  S. Klassen,et al.  Sodium nitroprusside activates p38 mitogen activated protein kinase through a cGMP/PKG independent mechanism. , 2007, Life sciences.

[20]  J. Haynes,et al.  Phosphorylation of the PKG substrate, vasodilator-stimulated phosphoprotein (VASP), in human cultured prostatic stromal cells. , 2007, Nitric oxide : biology and chemistry.

[21]  R. Schnellmann,et al.  Signaling of Mitochondrial Biogenesis following Oxidant Injury* , 2007, Journal of Biological Chemistry.

[22]  Jiahuai Han,et al.  Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin αIIbβ3 , 2006 .

[23]  F. Hofmann.  The Biology of Cyclic GMP-dependent Protein Kinases* , 2005, Journal of Biological Chemistry.

[24]  E. Clementi,et al.  Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E. Clementi,et al.  Mitochondrial Biogenesis in Mammals: The Role of Endogenous Nitric Oxide , 2003, Science.

[26]  R. Goldman,et al.  Nuclear lamins: building blocks of nuclear architecture. , 2002, Genes & development.

[27]  Jiandie D. Lin,et al.  Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. , 2001, Molecular cell.

[28]  R. Ye,et al.  Nitric Oxide Activation of p38 Mitogen-activated Protein Kinase in 293T Fibroblasts Requires cGMP-dependent Protein Kinase* , 2000, The Journal of Biological Chemistry.

[29]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[30]  R. Schnellmann,et al.  L-ascorbic acid regulates growth and metabolism of renal cells: improvements in cell culture. , 1996, The American journal of physiology.

[31]  Lothar Roessig,et al.  Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure. , 2017, Handbook of experimental pharmacology.