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Review
. 2022 May 17:13:821300.
doi: 10.3389/fphys.2022.821300. eCollection 2022.

Inducible Nitric Oxide Synthase/Nitric Oxide System as a Biomarker for Stress and Ease Response in Fish: Implication on Na+ Homeostasis During Hypoxia

M C Subhash Peter  1   2 , R Gayathry  1 , Valsa S Peter  1
Affiliations
Review

Inducible Nitric Oxide Synthase/Nitric Oxide System as a Biomarker for Stress and Ease Response in Fish: Implication on Na+ Homeostasis During Hypoxia

M C Subhash Peter et al. Front Physiol. .

Abstract

The cellular and organismal response to stressor-driven stimuli evokes stress response in vertebrates including fishes. Fishes have evolved varied patterns of stress response, including ionosmotic stress response, due to their sensitivity to both intrinsic and extrinsic stimuli. Fishes that experience hypoxia, a detrimental stressor that imposes systemic and cellular stress response, can evoke disturbed ion homeostasis. In addition, like other vertebrates, fishes have also developed mechanisms to recover from the impact of stress by way of shifting stress response into ease response that could reduce the magnitude of stress response with the aid of certain neuroendocrine signals. Nitric oxide (NO) has been identified as a potent molecule that attenuates the impact of ionosmotic stress response in fish, particularly during hypoxia stress. Limited information is, however, available on this important aspect of ion transport physiology that contributes to the mechanistic understanding of survival during environmental challenges. The present review, thus, discusses the role of NO in Na+ homeostasis in fish particularly in stressed conditions. Isoforms of nitric oxide synthase (NOS) are essential for the synthesis and availability of NO at the cellular level. The NOS/NO system, thus, appears as a unique molecular drive that performs both regulatory and integrative mechanisms of control within and across varied fish ionocytes. The activation of the inducible NOS (iNOS)/NO system during hypoxia stress and its action on the dynamics of Na+/K+-ATPase, an active Na+ transporter in fish ionocytes, reveal that the iNOS/NO system controls cellular and systemic Na+ transport in stressed fish. In addition, the higher sensitivity of iNOS to varied physical stressors in fishes and the ability of NO to lower the magnitude of ionosmotic stress in hypoxemic fish clearly put forth NO as an ease-promoting signal molecule in fishes. This further points to the signature role of the iNOS/NO system as a biomarker for stress and ease response in the cycle of adaptive response in fish.

Keywords: NOS; Na+/K+-ATPase; biomarker; ease response; fish; hypoxia; nitric oxide; stress response.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic chart showing the cyclic events associated with the adaptive response that happens in an organism when it encounters stressors such as hypoxia. In this cycle of adaptive response, the organism exhibits a basal homeostatic state due to its nonstressed condition (Panel 1.1). But later, the organism perceives stress stimulus from hypoxia. For example, when an air-breathing fish was held in water, it experienced hypoxia as a result of forceful submergence (immersion) (Panel 1.2). Here, the fish enters the stress phase and shows stress response (Panel 1.2). When these fish were treated with L-NAME, activation of the iNOS/NO system occurs in their ionocytes that induces multidimensional regulation of NKA. This brings a new drive to initiate ease response in this fish, though its contribution is little at that stage of the stress phase (Panel 1.2). However, in the next stage, the fish were able to utilize the fullest iNOS/NO system to lower the magnitude of the stress response as evident in the overlapping of the highest ring of ease response (Panel 1.3). In stage 3, the fish were able to show a substantial degree of ease response, though minimal stress response could also be sustained in that stage (Panel 1.4). While staying in this phase of ease, the fish could be brought back to its basal homeostasis stage (Panel 1.1). At this basal homeostatic stage, the fish could again experience another stress stimulus and corresponding stages could be achieved repeatedly by running the events of the cycle again. This constitutes the cycle of adaptive response with two phases, namely, stress and ease phase (Panel 1).
FIGURE 2
FIGURE 2
Chart showing the impact of hypoxemia stress on the activation of the iNOS/NO system in the ionocytes of fish. In fishes, varied isoforms of nitric oxide synthases: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) are involved in the production of NO from L-arginine in the presence of NADPH and O2. Upon induction of hypoxemia stress in an air-breathing fish (A. testudineus), activation of the iNOS/NO system occurs in branchial ionocytes. This leads to the differential regulation of NKA that ultimately contributes to the recovery of systemic Na+ balance.
FIGURE 3
FIGURE 3
Schematic chart showing the in vivo action of L-NAME on NKA dynamics and the iNOS/NO system in ionocytes of air-breathing fish A. testudineus under hypoxemia stress. Treatment of the nitric oxide synthase inhibitor, L-NAME, in non-stressed fish suppressed the NO release in the branchial, renal, and intestinal epithelia of this fish. But, L-NAME challenge in hypoxemia-stressed fish delivered more endogenous NO production in epithelial ionocytes due to the rise in inducible nitric oxide synthase (iNOS) protein abundance, especially in branchial and intestinal epithelia. This activation of the iNOS/NO system in hypoxic fish demands multidimensional regulation of NKA in these ionocytes This resistance response of the iNOS/NO system further allows the air-breathing fish to restore the compromised epithelial Na+ transport and defend against the life-threatening hypoxemia condition (adopted from Peter and Gayathry, 2021).
FIGURE 4
FIGURE 4
Typical homeostatic pattern of stress response involves NKA-driven Na+ homeostasis and ease response. Here, the response of NKA function was plotted when the fish was subjected to 30 min immersion stress against the nonstressed condition. The highest magnitude of ionosmotic stress response is represented as the highest peak in the parabola when the fish were held at a 30-min time frame. L-NAME–induced activation of the iNOS/NO system in the ionocytes of stressed fish initiated a recovery response by lowering the magnitude of NKA-driven Na+ transport. This ability of the iNOS/NO system to attenuate the hypoxemia-induced ionosmotic stress response depicts a major role of the iNOS/NO system as a biomarker for stress and ease response in fish.
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