H2S- and NO-releasing gasotransmitter platform: A crosstalk signaling pathway in the treatment of acute kidney injury

Abstract

Acute kidney injury (AKI) is a syndrome affecting most patients hospitalized due to kidney disease; it accounts for 15 % of patients hospitalized in intensive care units worldwide. AKI is mainly caused by ischemia and reperfusion (IR) injury, which temporarily obstructs the blood flow, increases inflammation processes and induces oxidative stress. AKI treatments available nowadays present notable disadvantages, mostly for patients with other comorbidities. Thus, it is important to investigate different approaches to help minimizing side effects such as the ones observed in patients subjected to the aforementioned treatments. Therefore, the aim of the current review is to highlight the potential of two endogenous gasotransmitters - hydrogen sulfide (H₂S) and nitric oxide (NO) - and their crosstalk in AKI treatment. Both H₂S and NO are endogenous signalling molecules involved in several physiological and pathophysiological processes, such as the ones taking place in the renal system. Overall, these molecules act by decreasing inflammation, controlling reactive oxygen species (ROS) concentrations, activating/inactivating pro-inflammatory cytokines, as well as promoting vasodilation and decreasing apoptosis, hypertrophy and autophagy. Since these gasotransmitters are found in gaseous state at environmental conditions, they can be directly applied by inhalation, or in combination with H₂S and NO donors, which are compounds capable of releasing these molecules at biological conditions, thus enabling higher stability and slow release of NO and H₂S. Moreover, the combination between these donor compounds and nanomaterials has the potential to enable targeted treatments, reduce side effects and increase the potential of H₂S and NO. Finally, it is essential highlighting challenges to, and perspectives in, pharmacological applications of H₂S and NO to treat AKI, mainly in combination with nanoparticulated delivery platforms.

Keywords: Acute kidney injury; Hydrogen sulfide; Nanomaterials; Nitric oxide.

Graphical abstract

Fig. 1

Effects of EDV and NO-EDV on cytokine production in kidney samples. TNF-α (a), IL-6 (b), IL-1β (c), and IL-18 (d) levels were measured in the kidney of sham-operated rats (sham) and rats that underwent 45 min ischemia and 6 h reperfusion in the absence (vehicle) or presence of EDV (1.2–30 μmol/kg, i.v.) or NO-EDV (0.3–6 μmol/kg, i.v.). Data are mean S.E.M. *P < 0.05 versus vehicle. Reproduced from Chiazza et al. 2015 under the Creative Commons Attribution License of open access article [88].

Fig. 2

Urine output (a) and creatinine clearance (b) in 16 anesthetized sheep subjected to left renal ischemia and reperfusion. Renal ischemia was caused by clamping of the renal artery for 90 min. Fifteen minutes prior to the release of the clamp, intravenous infusions with either the organic mononitrites of 1,2-propanediol (PDNO, n = 8) or vehicle (1,2-propanediol + inorganic nitrite, n = 8) were commenced. The infusions continued for 6 h. Data are expressed as mean and SEM. Significant (p < 0.05) differences in response to PDNO compared to vehicle is indicated by an asterisk. Reproduced from Nilsson et al. 2017 under the Creative Commons Attribution 4.0 License of open access article [89].

Fig. 3

Schematic representation of potential benefits of exogenous administration of H₂S and NO, and their beneficial effects in kidney.

Fig. 4

Schematic representation of the biosynthesis of NO, mediated by nitric oxide synthase isoforms: neuronal, inducible and endothelial (nNOS, iNOS, eNOS, respectively) and the biosynthesis of H₂S, mediated by cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfotransferase (CBS, CSE, 3-MST, respectively). Further, the products resultant from the interaction between the two signaling molecules are shown.

Fig. 5

Schematic representation of the chemical crosstalk between NO and H₂S. From the NO^• and HS^• the intermediates HSNO and HNO (nitroxyl) are formed, directly influencing in the protein functions by two distinct pathways: (i) induction of disulfide bonds and (ii) conversion of thiolated groups in cysteine residues to N-hydroxysulfenamide (RSNHOH).

Fig. 6

Schematic representation of the endogenous crosstalk between L-arginine/NO and L-cysteine/H₂S leading to an increased expression of cGMP and 5′GMP, with direct consequence in hyperpolarization and relaxation. 5′GMP: (5′ guanilyl monophosphate); cGMP: (cyclic guanilyl monophosphate); GTP: guanilyl triphosphate; NOS: nitric oxide synthase; CSE: cystathionine gamma lyase.