title: Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells.
abstract: Hydrogen sulfide, a signaling gas, affects several cell functions. We hypothesized that hydrogen sulfide modulates high glucose (30 mm) stimulation of matrix protein synthesis in glomerular epithelial cells. High glucose stimulation of global protein synthesis, cellular hypertrophy, and matrix laminin and type IV collagen content was inhibited by sodium hydrosulfide (NaHS), an H(2)S donor. High glucose activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), shown by phosphorylation of p70S6 kinase and 4E-BP1, was inhibited by NaHS. High glucose stimulated mTORC1 to promote key events in the initiation and elongation phases of mRNA translation: binding of eIF4A to eIF4G, reduction in PDCD4 expression and inhibition of its binding to eIF4A, eEF2 kinase phosphorylation, and dephosphorylation of eEF2; these events were inhibited by NaHS. The role of AMP-activated protein kinase (AMPK), an inhibitor of protein synthesis, was examined. NaHS dose-dependently stimulated AMPK phosphorylation and restored AMPK phosphorylation reduced by high glucose. Compound C, an AMPK inhibitor, abolished NaHS modulation of high glucose effect on events in mRNA translation as well as global and matrix protein synthesis. NaHS induction of AMPK phosphorylation was inhibited by siRNA for calmodulin kinase kinase β, but not LKB1, upstream kinases for AMPK; STO-609, a calmodulin kinase kinase β inhibitor, had the same effect. Renal cortical content of cystathionine β-synthase and cystathionine γ-lyase, hydrogen sulfide-generating enzymes, was significantly reduced in mice with type 1 diabetes or type 2 diabetes, coinciding with renal hypertrophy and matrix accumulation. Hydrogen sulfide is a newly identified modulator of protein synthesis in the kidney, and reduction in its generation may contribute to kidney injury in diabetes.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Hak Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Meenalakshmi M
authors.initials: MM
authors.lastname: Mariappan
authors.forename: Denis
authors.initials: D
authors.lastname: Feliers
authors.forename: Rita C
authors.initials: RC
authors.lastname: Cavaglieri
authors.forename: Kavithalakshmi
authors.initials: K
authors.lastname: Sataranatarajan
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D000393:Air Pollutants / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019757:Carbon-Oxygen Lyases; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005947:Glucose / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D053644:Naphthalimides / Q000494:pharmacology; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013549:Sweetening Agents / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000393:Air Pollutants; D001562:Benzimidazoles; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C499526:Eif4ebp1 protein, rat; D004791:Enzyme Inhibitors; D039642:Eukaryotic Initiation Factors; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D053644:Naphthalimides; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; C458525:STO 609; D013549:Sweetening Agents; C022696:O-succinylhomoserine (thiol)-lyase; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C491654:Stk11 protein, mouse; C488755:Stk11 protein, rat; D058570:TOR Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D019757:Carbon-Oxygen Lyases; D003541:Cystathionine beta-Synthase; D005947:Glucose; D006862:Hydrogen Sulfide