西亚试剂：Hydrogen sulfide inhibits high glucose-induced matrix prote

Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells

H. J. Lee, M. M. Mariappan, D. Feliers, R. C. Cavaglieri, K. Sataranatarajan, H. E. Abboud, G. Ghosh Choudhury, B. S. Kasinath.

Capsule: Background: If hydrogen sulfide regulates protein synthesis is not known. Results: In kidney cells, hydrogen sulfide inhibited high glucose-induced synthesis of proteins including matrix proteins by activating AMP-activated protein kinase and inhibiting events in mRNA translation. Conclusion: Hydrogen sulfide reduces high glucose stimulation of matrix protein synthesis in renal cells. Significance: Hydrogen sulfide induction may inhibit kidney matrix protein accumulation in diabetes. Abstract: Hydrogen sulfide, a signaling gas, affects several cell functions. We hypothesized that hydrogen sulfide modulates high glucose (HG, 30 mM) stimulation of ma-trix protein synthesis in glomerular epithelial cells (GECs). HG stimulation of global protein synthesis, cel-lular hypertrophy, and matrix laminin and type IV col-lagen content was inhibited by NaHS, a H2S donor. HG activation of mTOR complex1 (mTORC1), shown by phosphorylation of p70S6 kinase and 4E-BP1, was in-hibited by NaHS. HG recruited mTORC1 to promote key events in the initiation and elongation phases of mRNA translation: binding of eIF4A to eIF4G, reduc-tion in PDCD4 expression and inhibition of its binding to eIF4A, eEF2 kinase phosphorylation and dephos-phorylation of eEF2; these events were inhibited by NaHS. Role of AMPK, an inhibitor of protein synthesis, was examined. NaHS dose-dependently stimulated AMPK phosphorylation and restored AMPK phos-phorylation reduced by HG. Compound C, an AMPK inhibitor, abolished NaHS effect on events in mRNA translation as well as global and matrix protein synthe-sis. NaHS induction of AMPK phosphorylation was in-hibited by siRNA for Ca calmodulin kinase kinase beta (CaMKKbeta), but not LKB1, upstream kinases for AMPK; STO-609, a CaMKKbeta inhibitor, had the same effect. Renal cortical content of cystathionine beta synthase and cystathionine gamma lyase, hydrogen sulfide generating enzymes, was significantly reduced in mice with type 1 diabetes or type 2 diabetes, coinciding with renal hyper-trophy 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.

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