Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3

Abstract

Diabetic kidney disease is known as a major cause of chronic kidney disease and end stage renal disease. Polysulfides, a class of chemical agents with a chain of sulfur atoms, are found to confer renal protective effects in acute kidney injury. However, whether a polysulfide donor, sodium tetrasulfide (Na 2 S 4 ), confers protective effects against diabetic nephropathy remains unclear. Our results showed that Na 2 S 4 treatment ameliorated renal dysfunctional and histological damage in diabetic kidneys through inhibiting the overproduction of inflammation cytokine and reactive oxygen species (ROS), as well as attenuating renal fibrosis and renal cell apoptosis. Additionally, the upregulated phosphorylation and acetylation levels of p65 nuclear factor κB (p65 NF-κB) and signal transducer and activator of transcription 3 (STAT3) in diabetic nephropathy were abrogated by Na 2 S 4 in a sirtuin-1 (SIRT1)-dependent manner. In renal tubular epithelial cells, Na 2 S 4 directly sulfhydrated SIRT1 at two conserved CXXC domains (Cys371/374; Cys395/398), then induced dephosphorylation and deacetylation of its targeted proteins including p65 NF-κB and STAT3, thereby reducing high glucose (HG)-caused oxidative stress, cell apoptosis, inflammation response and epithelial-to-mesenchymal transition (EMT) progression. Most importantly, inactivation of SIRT1 by a specific inhibitor EX-527, small interfering RNA (siRNA), a de-sulfhydration reagent dithiothreitol (DTT), or mutation of Cys371/374 and Cys395/398 sites at SIRT1 abolished the protective effects of Na 2 S 4 on diabetic kidney insulting. These results reveal that polysulfides may attenuate diabetic renal lesions via inactivation of p65 NF-κB and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1.

Update on the Mechanisms of Tubular Cell Injury in Diabetic Kidney Disease

“…Also, the role of SS31 has been associated with CD36 ( 58 ). Besides, Na2S4, a polysulfide donor that directly sulfhydrates SIRT1, reduces high glucose-induced oxidative stress, cell apoptosis, inflammatory response in renal tubular epithelial cells, and the progression of epithelial-to-mesenchymal transition (EMT) ( 59 ). Also, Carnosine has been shown to significantly decrease the production of ROS, alleviate oxidative stress, and inhibit apoptosis through mitochondrial pathway in vitro ( 60 ) and in vivo ( 61 ).…”

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

“…The pathological processes that drive podocyte dysfunction involve sirtuin 1 (SIRT1), a deacetylase that regulates cell inflammation, apoptosis, proliferation, autophagy, energy metabolism, and oxidative stress [ 13 ]. SIRT1 appears to exert a renoprotective effect in kidney diseases, including DN [ 14 – 16 ]. 3,5-Diiodothyronine can inhibit mesangial cell proliferation and decrease proteinuria by activating SIRT1 in rat mesangial cells [ 17 ].…”

The Hidden Role of Hydrogen Sulfide Metabolism in Cancer

“…H 2 S regulates diverse cellular signaling pathways through persulfidation (S-sulfhydration) [ 3 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. This novel and reversible posttranslational modification covalently adds a thiol group (-SH) to active cysteine residue (PSH/PS - ) in its target protein, which forms protein persulfidation (PSSH/PSS - ) ( Figure 1 A) [ 46 ].…”