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

Abstract

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H₂S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H₂S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H₂S production by renal cells is reduced under disease states and H₂S donors ameliorate kidney injury. Specifically, aberrant H₂S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H₂S in diabetic renal disease and the underlying mechanisms for the protective effects of H₂S against diabetic renal damage. H₂S may serve as fundamental strategies to treat diabetic kidney disease. These H₂S treatment modalities include precursors for H₂S synthesis, H₂S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H₂S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H₂S in the kidney may be vital to translate H₂S to be a novel therapy for diabetic renal disease.

Keywords: diabetic nephropathy; hydrogen sulfide; oxidative stress; renal physiology; renin-angiotensin system.

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.

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.

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.

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.

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.

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.

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.