Involvement of Hydrogen Sulfide in the Progression of Renal Fibrosis

0
0
0

Involvement of Hydrogen Sulfide in the Progression of Renal Fibrosis

Chronic kidney disease (CKD) represents a significant global health challenge, affecting approximately 11% of the global population. Renal fibrosis, a hallmark of CKD, involves the irreversible replacement of functional kidney tissue with scar tissue, driven by complex interactions between cellular components and signaling pathways. Despite current therapies that slow disease progression, there remains an unmet need for treatments that halt or reverse fibrosis. Recent research highlights hydrogen sulfide (H2S), a gaseous signaling molecule, as a potential therapeutic agent targeting multiple pathologic mechanisms underlying renal fibrosis.

Hydrogen Sulfide: A Multifaceted Signaling Molecule

H2S, once regarded as a toxic gas, is now recognized as a critical endogenous regulator of physiologic and pathologic processes. It is synthesized enzymatically from L-cysteine and D-cysteine via cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in the kidney. CBS predominates in proximal tubules, while CSE is expressed in glomerular endothelial cells, mesangial cells, and podocytes. Dysregulation of these enzymes correlates with CKD progression, as observed in diabetic nephropathy and hypertensive kidney injury, where oxidative stress and hyperhomocysteinemia reduce H2S production.

H2S exerts pleiotropic effects, including vasodilation, regulation of glomerular filtration rate (GFR), sodium excretion, and oxygen sensing. It also modulates epigenetic mechanisms, such as DNA methylation and histone deacetylation, influencing genes like CSE. In CKD models, H2S deficiency exacerbates renal damage, while supplementation ameliorates fibrosis by targeting inflammation, oxidative stress, fibroblast activation, and vascular remodeling.

Mechanisms of H2S in Attenuating Renal Fibrosis

1. Suppression of Inflammation

Inflammation initiates and perpetuates renal fibrosis. In unilateral ureteral obstruction (UUO) models, low-dose H2S reduces infiltration of CD68+ macrophages and shifts macrophage polarization toward the anti-inflammatory M2 phenotype. H2S downregulates pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1), while inhibiting nuclear factor-κB (NF-κB) signaling. In diabetic nephropathy, H2S reverses angiotensin II (Ang II)-induced inflammation by modulating miR-129 via epigenetic regulation. These anti-inflammatory actions disrupt the crosstalk between inflammatory cells and fibroblasts, reducing pro-fibrotic cytokine release.

2. Mitigation of Oxidative Stress

Oxidative stress, driven by NADPH oxidases (NOX) and mitochondrial dysfunction, is central to fibrosis. H2S scavenges reactive oxygen species (ROS), enhances antioxidant defenses (e.g., superoxide dismutase, glutathione), and activates nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant genes. In streptozotocin (STZ)-induced diabetic rats, H2S decreases renal NOX4 expression via AMP-activated protein kinase (AMPK) activation, reducing matrix protein accumulation. Additionally, H2S upregulates heme oxygenase-1 (HO-1) and sirtuin 1 (SIRT1), further counteracting oxidative damage.

3. Inhibition of Fibroblast Activation and Epithelial-Mesenchymal Transition (EMT)

Myofibroblasts, derived from fibroblasts, pericytes, and tubular epithelial cells via EMT, are primary contributors to extracellular matrix (ECM) deposition. Transforming growth factor-β1 (TGF-β1) activates fibroblasts through Smad2/3 phosphorylation and mitogen-activated protein kinase (MAPK) pathways. H2S blocks TGF-β1 signaling by suppressing Smad3 phosphorylation, increasing Smad7 (an inhibitory Smad), and inhibiting TGF-β receptor I/II expression. In Ang II-induced models, H2S attenuates EMT by reducing β-catenin nuclear translocation and ERK phosphorylation. Furthermore, H2S downregulates matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which degrade ECM but paradoxically promote fibrosis in chronic injury.

4. Amelioration of Vascular Remodeling and Hypertension

Hypertension and peritubular capillary loss accelerate renal fibrosis. H2S induces vasodilation by activating ATP-sensitive potassium (KATP) channels in vascular smooth muscle cells, enhancing renal blood flow and medullary oxygenation. It also inhibits vascular smooth muscle cell proliferation and calcification by suppressing ERK/MAPK signaling and osteoblastic differentiation. In Dahl salt-sensitive rats, H2S donors lower blood pressure by reducing angiotensin II levels and inhibiting the renin-angiotensin-aldosterone system (RAAS). H2S further ameliorates endothelial dysfunction by modulating the BMP4/COX-2 pathway, highlighting its role in preserving renal microvasculature.

5. Regulation of Tubular Cell Fate: Apoptosis, Autophagy, and Regeneration

Proximal tubule injury drives fibrosis through apoptosis, autophagy, and failed repair. H2S exhibits context-dependent effects: it promotes tubular regeneration post-ischemia/reperfusion but reduces apoptosis in UUO models. In diabetic kidneys, H2S inhibits autophagy by downregulating AMPK and mTORC1 signaling, preventing epithelial cell hypertrophy and matrix protein overproduction. However, excessive H2S may exacerbate cisplatin-induced nephrotoxicity by promoting oxidative stress, underscoring the need for precise dosing.

Therapeutic Potential and Clinical Translation

H2S donors are classified into natural (e.g., garlic derivatives) and synthetic compounds. Early donors like sodium hydrosulfide (NaHS) release H2S rapidly but transiently. Slow-releasing donors, such as GYY4137 and mitochondria-targeted AP39, provide sustained H2S delivery with reduced off-target effects. Clinical trials investigating H2S-based therapies include:

  • SG-1002 (sodium polysulfonate): A phase II trial for heart failure, demonstrating antioxidant and anti-inflammatory effects.
  • IK-1001 (intravenous sodium sulfide): Tested for cardioprotection in myocardial infarction, though limited by assay challenges.
  • ATB-346 (H2S-releasing NSAID): Reduces gastrointestinal toxicity while maintaining efficacy.

Despite promising preclinical data, challenges persist in optimizing donor pharmacokinetics, minimizing toxicity, and validating biomarkers for H2S bioavailability. Combining H2S donors with RAAS inhibitors or antifibrotic agents (e.g., fluorofenidone) may enhance efficacy.

Limitations and Future Directions

Current studies face methodological limitations, including unreliable H2S measurement techniques and inconsistent enzyme expression data. For instance, conflicting reports on CSE localization in glomeruli warrant clarification using advanced methods like laser-capture microdissection. Additionally, the dual role of H2S in autophagy and apoptosis requires further exploration across disease stages.

Future research should:

  1. Elucidate H2S interactions with mitochondrial biogenesis regulators (e.g., PGC-1α).
  2. Develop kidney-targeted H2S donors to minimize systemic effects.
  3. Investigate H2S epigenetic regulation in fibroblast reprogramming.
  4. Validate clinical endpoints in CKD cohorts, focusing on fibrosis regression and GFR preservation.

Conclusion

Hydrogen sulfide emerges as a multifaceted therapeutic candidate for renal fibrosis, targeting inflammation, oxidative stress, fibroblast activation, and vascular dysfunction. Preclinical studies underscore its potential to delay CKD progression, but clinical translation requires addressing pharmacokinetic challenges and optimizing donor specificity. As the understanding of H2S biology evolves, its integration into combination therapies may offer a transformative approach to mitigating renal fibrosis.

doi.org/10.1097/CM9.0000000000000537

Was this helpful?

0 / 0