Hydrogen Sulfide: Recent Progression and Perspectives for the Treatment of Diabetic Nephropathy

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  Figure 1. Conventional pathophysiology of diabetes kidney disease. Diabetic kidney disease is closely associated with renal hemodynamic changes, ischemia and glucose metabolism abnormalities, oxidative stress, inflammatory response and over-activated RAAS, which contributes to glomerular hypertension and sclerosis, tubulointerstitial fibrosis, tubular atrophy and mesangial cell expansion. RAAS, renin-angiotensin-aldosterone system; IGF-1, insulin-like growth factor 1; TGF-β1, transforming growth factor β1; VEGF, vascular endothelial growth factor; PG, prostaglandin; Ang II, angiotensin II; ET-1, endothelin-1; SGLT2, sodium glucose co-transporters 2; ROS, reactive oxygen species; AGEs, advanced glycation end products; TNF-α, tumor necrosis factor α; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; HIF, hypoxia-inducible factor; ECM, extracellular matrix; JAK/STAT, Janus kinase-signal transducer and activator transcription factor; MCP-1, monocyte chemotactic protein 1.

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  Figure 2. Endogenous synthesis of H2S in renal system. (A) CSE reacts with L-homocysteine to induce H2S generation accompanied by formation of α-ketobutyrate and L-homolanthionine. CBS catalyzes L-homocysteine that leads to the production of L-cystathionine, which is converted into L-cysteine by CSE. The presence of L-cysteine serves as a substrate for generation of H2S by CBS and CSE. (B) L-Cysteine translocates to mitochondria, followed by conversion to 3-MP by CAT. 3-MST produces H2S generation from 3-MP. (C) Peroxisome-mediated generation of 3-MP from D-cysteine with the aid of DAO. 3-MP is then imported into the mitochondria and becomes a substrate for 3-MST to generate H2S. CBS, cystathionine β-synthase; CSE, cystathionine g-lyase; 3-MST, 3-mercaptopyruvatesulfurtransferase; CAT, cysteine aminotransferase; DAO, D-amino acidoxidase; 3-mercapto pyruvate, 3-MP.

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  Figure 3. A proposed sketch showing the effect of H2S on the renin-angiotensin-system (RAS). Angiotensinogen is cleaved by renin to produce angiotensin I, then angiotensin I is further converted to Ang II by ACE. The deleterious effects of Ang II are mediated by AT1 receptors, whereas Ang II acts on AT2 receptors to function as a negative modulator of AT1 receptor actions. The activated RAS in diabetic kidney disease was ameliorated by H2S treatment via inhibition of angiotensinogen, ACE, Ang II and AT1 receptors. RAS, renin-angiotensin-system; ACE, angiotensin converting enzyme; Ang II, angiotensin II.

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  Figure 4. Effects of H2S on oxidative stress in diabetes kidney disease. H2S is found to reduce high glucose-induced oxidative stress by activating the Nrf2 antioxidant pathway and two downstream targets of Nrf2, HO-1 and NQO1, as well as enhancing the SOD and glutathione peroxidase activities in diabetes kidney disease. Nrf2, nuclear factor erythroid-2 related factor 2; HO-1, heme oxygenase-1; NQO1, NADPH: quinone oxidoreductase-1; SOD, superoxide dismutase.

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  Figure 5. A proposed model of diabetic kidney inflammation mediated by H2S. The anti-inflammation mechanisms of H2S may involve its inhibition of macrophages infiltration, as well as its blockade of NF-κB and MAPK signaling in renal system. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase, TNF-α, tumor necrosis factor α; IL-1β, interleukin-1β; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1; MCP-1, monocyte chemotactic protein-1; MMP-9, matrix metalloproteinase-9.

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  Figure 6. Effect of H2S on renal fibrosis in diabetic kidneys. Activated fibroblasts may be from resident quiescent fibroblasts via the process of EndMT. H2S treatment prevents the differentiation of quiescent renal fibroblasts to myofibroblasts and myofibroblasts proliferation via inhibition of the TGF-β1/Smad and MAPK signaling pathways. Blockade of ERK- and β-catenin-dependent pathways may be involved in the protective effect of H2S on the formation of EMT in renal tubular epithelial cells. In addition, H2S dose-dependently stimulates AMPK phosphorylation and induces its subsequent inhibition of mTORC1 activity. Induction of iNOS, is required for H2S to inhibit high glucose-induced oxidative stress and matrix protein generation in renal proximal tubular epithelial cells. EndMT, endothelial-mesenchymal transition; EMT, epithelial mesenchymal transition; TGF-β1, transforming growth factor-β1; MAPK, mitogen-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; ERK, extracellular regulated protein kinases; AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase; iNOS, inducible nitric oxide synthase.

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  Figure 7. Effect of H2S on glomerular hypertrophy and podocyte injury in diabetic kidneys. (A) Activation of intrarenal renin-angiotensin system and NADPH-derived ROS contribute to the proliferation and ECM secretion in high glucose-incubated renal mesangial cells, this phenomenon is attenuated by H2S, dependent on HO-1 induction and inhibition of TLR4 and PI3K/Akt pathway. (B) Further studies reveal that endoplasmic reticulum stress, dysregulation of autophagy and mTORC1 activation in podocyte promote the development of diabetic nephropathy. H2S may induce AMPK phosphorylation and HO-1, and suppress the Wnt/β-catenin pathway to mitigate podocyte injury induced by hyperglycemia. NADPH, reduced nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; ECM, extracellular matrix; HO-1, heme oxygenase-1; TLR4, toll-like receptor 4; mTORC1, mammalian target of rapamycin (mTOR) complex 1; AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase.