Several lines of evidence indicate that NO, CO, and H₂S play key roles in the pathogenesis of hypertension. The first are observations on knockout mice lacking genes responsible for gasotransmitter synthesis. First, eNOS knockout mice displayed hypertension [55]. The importance of H₂S-generating enzymes in hypertension has also been demonstrated using CSE, CBS, or 3MST knockout mice [47,56,57,58]. Another report showed male HO-2 knockout mice are prone to develop renovascular hypertension [59].

The second line of evidences report dysregulated gasotransmitter signaling pathways in human and experimental models of hypertension. Prior research has addressed impaired L-Arginine–ADMA–NO pathway in the development of hypertension [60]. Dysregulated HO-1–CO pathway was reported to induce vascular dysfunction and hypertension in various animal models [61]. Likewise, deficiencies in H₂S-generating enzymes and/or activity in hypertension has been established in various animal models, including the NO-deficient rats [62], the Dahl salt-sensitive rats [63], the spontaneously hypertensive rat (SHR) [64], and the renovascular hypertensive model [65].

Third, several therapeutic strategies targeting different gasotransmitters have demonstrated to be significant promising for beneficial effects against hypertension in various animal models [60,61,66,67,68].

The gasotransmitter generating enzymes iNOS, eNOS, nNOS, HO-1, HO-2, CSE, CBS, and 3MST were detected in kidney cells comprising podocytes, glomerular endothelial cells, tubular cells, and mesangial cells, but not all of them are constitutively expressed in every cell type [69,70]. For example, eNOS is expressed in the glomerular endothelial cells, peritubular capillaries, and vascular bundles, while nNOS is mainly detected in the tubular epithelial cells of the macula densa [70]. Of note, iNOS and HO-1 are not constitutively expressed in the kidney but only expressed under certain pathophysiological conditions like inflammation [70].

In the kidney, NO performs important signaling functions including the modulation of renal sympathetic neural activity, control of renal hemodynamics, regulation of pressure-natriuresis, blunting of tubuloglomerular feedback, and inhibition of tubular sodium reabsorption [70]. Accordingly, impaired NO signaling has been implicated in the pathogenesis of kidney diseases. As reviewed elsewhere [14,71], kidney injury is attributed to NO deficiency in a variety of CKD models, such as diabetic nephropathy, chronic glomerular nephritis, the 5/6 nephrectomy model, the aging kidney, the Zucker obese rat, chronic allograft nephropathy, etc.

The beneficial actions of CO in the kidney have also been recognized [15]. Inhibition of superoxide production, activation of sGC, stimulation of NO production, and stimulation of p38 mitogen-activated protein kinase (MAPK) pathway are all examples of the beneficial effects of CO in the kidney to protect the kidney [15]. Deficiency or inhibition of HO-1 in animal models worsens renal structure and function, while increased expression is protective [72]. So far, evidences from animal models indicate that several kidney diseases have been associated with impaired HO-1 or -2 system, including diabetic nephropathy [73], lupus nephritis [74], nephrotoxic nephritis [75], ischemia-reperfusion injury [76], obstructive nephropathy [77], and CKD [78].

H₂S regulates basic physiologic mechanisms of the kidney such as sodium reabsorption, glomerular filtration, and renal homeostasis [17]. In some animal models of kidney disease, such as CKD [79], acute kidney injury [80], cisplatin nephropathy [81], obstructive nephropathy [82], and diabetic nephropathy [83], it can serve as an agent that ameliorates kidney injury.

Although NO and H₂S share the same sGC–cGMP pathway to elicit relaxation in kidney cells [16], they act at different levels, with NO increasing production of cGMP through stimulation of sGC and H₂S inhibiting cGMP degradation [84]. In rats, inhibition of NO by L-NAME, causes hypertension that can be prevented by the administration of sodium hydrosulfide (NaHS, a H₂S donor), which also rescues NO bioavailability [85]. These data support the notion that there exists a NO/H₂S crosstalk in the control of blood pressure (BP).

One of the NO-based cellular signaling pathways is via protein S-nitrosylation, the covalent addition of NO moiety to the sulfur atom of cysteine residues [86]. S-nitrosylation of specific proteins has been shown to be protective against kidney injury [86]. As observed for NO, H₂S also employs post-translational modifications, namely, S-sulfhydration [87]. Endogenous H₂S physiologically S-sulfydrates proteins on the thiol group of cysteine residues (e.g., glutathione), leading to the formation of the –SSH moiety. These observations lead to a hypothesis that there might be competition between S-nitrosylation and S-sulfhydration for the same cysteine residues in proteins, thus allowing the two gasotransmitters to regulate each other [84].

CO could also target sGC and regulate NO-mediated vasodilatation [88], which was supported by a report showing that transgenic mice overexpressing cell-specific HO-1 exhibit hypertension coinciding with decreased cGMP production in response to NO [89]. Additionally, CO could interfere with NOS activity and reduce NO generation as a consequence, thereby limiting NO-mediated vasodilation [90]. Although much is known about the CO and NO signaling pathways in the kidney, we so far do not fully understand how these two gaseous signaling systems interact with each other.

Moreover, all three gasotransmitters are involved in activation of nuclear factor erythroid 2-related factor 2 (NRF2) (Figure 2). NRF2 is a major regulator of HO-1 transcription responding to oxidative stress [72]. Upon activation, the NRF2-HO-1 pathway protects chronic kidney disease progression related to reduction of oxidative stress, inhibition of transforming growth factor-β (TGF-β)-driven fibrosis, reduction of inflammation and apoptosis [91]. Under basal conditions, NRF2 levels are kept low through the interaction with Kelch-like ECH associated protein 1 (KEAP1). Upon binding, the NRF2-KEAP1 interaction stabilizes the complex allowing for ubiquitylation, and ultimately proteasomal degradation of NRF2 [91]. Of note, NO and H₂S can activate NRF2 via S-nitrosylation and S-sulfhydration of KEAP1, respectively [92,93]. In addition to NRF2, NO can regulate other redox-regulatory transcription factors, like nuclear factor κB (NFκB) and hypoxia-inducible factor-1α (HIF-1α), via S-nitrosylation [92]. As NFκB mediates inflammation and HIF-1α induces HO-1 expression, NO can interact with the NRF2–HO-1–CO signaling pathway in many different ways to prevent CKD progression. NFκB can also be S-sulfhydrated by H₂S [93]. These observations indicate crosstalk mechanisms between NO, CO, and H₂S are important determinants for kidney disease (Figure 2).

Although the beneficial actions of gasotransmitters against established kidney disease and hypertension have been established, their roles in mediating programmed responses behind developmental origins remain unclear. For this reason, this review will next outline the potential early-life interventions targeting NO, CO, and H₂S signaling that may pose new opportunities for the therapeutic protection of hypertension and kidney disease.