Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis

Abstract

Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (H₂S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The pathophysiological link of this crosstalk is represented by oxidative stress and inflammatory processes which contribute to the high prevalence of neuropsychiatric disorders, cognitive impairment, and dementia during the natural history of chronic kidney disease. Herein, we provide an overview of the main pathophysiological mechanisms related to high levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and neurotoxins, which play a critical role in the kidney-brain crosstalk. The present paper also explores the respective role of H₂S and carnosine in the modulation of oxidative stress and inflammation in the kidney-brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.

Keywords: carnosine; hydrogen sulfide; inflammation; kidney–brain axis; oxidative stress; vitagenes.

Figure 1

Nutraceutical support of intracellular H₂S synthesis via cysteine metabolism. S-adenosyl homocysteine hydrolase (SAH), Cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), Cystathionine gamma lyase (CSE), Cysteine sulfinate (CSA), Hypotaurine dehydrogenase (HTD), Glutamate cysteine ligase (GCL), Glutathione synthetase (GS), Glycine (Gly).

Figure 2

The kidney–brain crosstalk by the H₂S signaling pathway. γ-glutamyl transpeptidase (γGGT) (3), γ-glutamyl cyclotransferase (4), dipeptidase (5), oxoprolinase (6), γ-glutamyl-cysteine synthase (1), and glutathione synthetase (2) operate in the Meister cycle to generate glutathione (GSH) and internalize amino acids (AA).

Figure 3

The modulation of the Nrf2-vitagene pathway by H₂S. In physiological conditions, Nrf2 is bound to its inhibitor Keap1 and is restricted to the cytosol where it undergoes ubiquitination and proteasomal degradation via association with the Cul3-Rbx1-based E3/ubiquitin ligase complex. Under stress conditions, Nrf2 is released from Keap1 and is translocated into the nucleus where it binds to the phase 2 of ARE in heterodimeric combination with the Maf transcription factor in the DNA promoter region. The H₂S antioxidant molecule blocks oxidative stress and NLRP3 inflammasome cascade by activating Nrf2 nuclear translocation and the transcription of cytoprotective (phase 2) vitagenes. The upregulation of the vitagene pathway such as HO-1, Hsp70, Trx, sirtuin Sirt1, NQO1, and γ-GCS improves brain health in neurological disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), antioxidant response element (ARE), heme-oxygenase 1 (HO-1), heat shock protein 70 (Hsp70), thioredoxin (Trx), sirtuin 1 (Sirt1), NAD(P)H: quinone oxidoreductase 1 (NQO1), γ-glutamylcysteine synthetase (γ-GCS).

Figure 4

Schematic representation of the carnosine, glutathione, and hydrogen sulfide (H₂S) pathways in the kidney-brain axis. γ-glutamyl transpeptidase (GGT) (3), γ-glutamyl cyclotransferase (4), dipeptidase (5), oxoprolinase (6), γ-glutamyl-cysteine synthase (1), and glutathione synthetase (2) operate in the Meister cycle to generate glutathione (GSH) and internalize amino acids (AA). GSH interacts with Cystathionine-β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3MST) to produce H₂S.