High Glucose Induces Mouse Mesangial Cell Overproliferation via Inhibition of Hydrogen Sulfide Synthesis in a TLR-4-Dependent Manner

Abstract

Background/Aims: Overproliferation of mesangial cells was believed to play an important role in the progress of diabetic nephropathy, one of the primary complications of diabetes. Hydrogen sulfide (H₂S), a well-known and pungent gas with the distinctive smell of rotten eggs, was discovered to play a protective role in diabetic nephropathy. Methods: MTT assay was used to examine the viability of mesangial cells. Small interfering RNA was used to knock down the expression of TLR4 while specific inhibitor LY294002 to suppress the function of PI3K. H₂S generation rate was determined by a H₂S micro-respiration sensor. Results: Glucose of 25mM induced significant mesangial cells proliferation, which was accomplished by significantly inhibited endogenous H₂S synthesis. And exogenous H₂S treatment by NaHS markedly mitigated the overproliferation of mouse mesangial cells. Furthermore, it was found that H₂S deficiency could result in TLR4 activation. And H₂S supplementation remarkably inhibited TLR4 expression and curbed the mesangial cell overproliferation. Besides, PI3K/Akt pathway inhibition also significantly ameliorated the cell overproliferation. Conclusion: High glucose (HG) induces mouse mesangial cell overproliferation via inhibition of hydrogen sulfide synthesis in a TLR-4-dependent manner. And PI3K/Akt pathway might also play a vital part in the HG-induced mesangial cell overproliferation.

TLR2 and TLR4 interact with sulfide system in the modulation of mouse colonic motility

“…In fact, H 2 S donors are able to reduce the infiltration of neutrophils and lymphocytes in several models and reduce the expression of many pro‐inflammatory cytokines, most likely related to its ability to suppress the activation of NF‐κB, a factor regulated by TLR2/TLR4 signaling . In addition, H 2 S supplementation inhibited TLR4 expression in a mouse model of mesangial cell overproliferation induced by high glucose . These evidences suggest that H 2 S is able to regulate TLR expression, although this regulation seems to be specific for the different tissues, species or models used.…”

“…31 In addition, H 2 S supplementation inhibited TLR4 expression in a mouse model of mesangial cell overproliferation induced by high glucose. 32 These evidences suggest that H 2 S is able to regulate TLR expression, although this regulation seems to be specific for the different tissues, species or models used.…”

Hydrogen Sulfide Inhibits High Glucose-Induced sFlt-1 Production via Decreasing ADAM17 Expression in 3T3-L1 Adipocytes

“…It also raises the possibility of the use of NaHS as a potential therapeutic agent for high glucose-induced ADAM17 expression and sFlt-1 production. Although the inhibition effect of high glucose on H 2 S production has been demonstrated in several different types of cells [15, 27, 28], the mechanisms responsible for high glucose on H 2 S synthase remain unclear. It has been reported that high glucose inhibited H 2 S production via TLR4 inflammatory pathway in mouse mesangial cells [28].…”

“…Although the inhibition effect of high glucose on H 2 S production has been demonstrated in several different types of cells [15, 27, 28], the mechanisms responsible for high glucose on H 2 S synthase remain unclear. It has been reported that high glucose inhibited H 2 S production via TLR4 inflammatory pathway in mouse mesangial cells [28]. In addition, the expression of several microRNAs, including miR-192 [29], miR-204 [30], and miR-217 [31], was upregulated by high glucose.…”

Transient High-Glucose Stimulation Induces Persistent Inflammatory Factor Secretion from Rat Glomerular Mesangial Cells via an Epigenetic Mechanism

“…However, the mechanism underlying the pathogenesis of DN is incompletely resolved, and there is no specific drug for the treatment and prevention of the development of DN, which has become a worldwide burden on public health. Recently, dysfunction of glomerular mesangial cells has been suggested to play a vital role in the pathogenesis of DN [3]_ENREF_3. Actually, even with strict control of plasma glucose, many diabetic patients eventually develop DN.…”