Transcriptomic Analysis Reveals that Activating Transcription Factor 3/c-Jun/Lgals3 Axis Is Associated with Central Diabetes Insipidus after Hypothalamic Injury

Abstract

Background: Hypothalamic injury causes several complicated neuroendocrine-associated disorders, such as water-electrolyte imbalance, obesity, and hypopituitarism. Among these, central diabetes insipidus (CDI), characterized by polyuria, polydipsia, low urine specific gravity, and deficiency of arginine vasopressin contents, is a typical complication after hypothalamic injury. Methods: CDI was induced by hypothalamic pituitary stalk injury in male animals. Behavioral parameters and blood sample were collected to evaluate the characteristics of body fluid metabolism imbalance. The brains were harvested for high-throughput RNA sequencing and immunostaining to identify pathophysiological changes in corresponding hypothalamic nuclei. Results: Based on transcriptomic analysis, we demonstrated the upregulation of the Atf3/c-Jun axis and identified Lgals3, a microglial activation related gene, as the most significant target gene in response to the body fluid imbalance in CDI. Furthermore, we found that the microglia possessed elevated phagocytic ability, which could promote the elimination of arginine vasopressin neurons after hypothalamic injury. Conclusion: Our findings suggested that the Atf3/c-Jun/Lgals3 axis was associated with the microglial activation, and might participate in the loss of functional arginine vasopressin neurons in CDI after hypothalamic injury.

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

“…For the lesion surgery, a stereotaxic apparatus was used. The coordinates of the ARC and VMH were determined based on previous research by our research group and the Paxinos and Watson rat brain atlas ( Roth et al, 2011 ; Feng et al, 2018a ; Zhou M. F. et al, 2019 ; Zhou et al, 2021 ). The Bregma point (AP: –2.6 mm, ML: ±0.6 mm, DV: –9.6 mm) was used as the target lesion point.…”

The multifaceted roles of activating transcription factor 3 (ATF3) in inflammatory responses – Potential target to regulate neuroinflammation in acute brain injury

“…51 Notably, the ATF3/c-Jun/Lgals3 axis may enhance microglial activation in central diabetes insipidus following hypothalamic damage. 52…”

“…101,102 Subsequently, the activation of cerebral resident neural and peripheral immune cells amplifies neuroinflammatory responses due to the compromised permeability of the blood brain barrier (BBB) and the proinflammatory cytokine storm. 103,104 Evidence shows that ATF3 can be expressed in microglia, 105,106 brain ECs, 67,107 and neurons 9,108 in the CNS and can exert effects on neuroinflammatory modulators to affect brain physiologic function or development. 31,32 Similarly, the expression of ATF3 in peripheral immune cells, such as macrophages, is involved in peripheral inflammation.…”

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP‐deficiency and resistance)

“…Other drugs such as penicillins, tetracyclines, aminoglycosides and anti‐fungals can also induce NDI (Table 3). 33,116–119 Cidofovir 96 and foscarnet, 120 as well as other anti‐retroviral drugs and AVPR2 antagonists such as tolvaptan, can also induce a transient state of NDI 121–123 . In the distal nephron, somatostatin analogues may also inhibit AVP action and increase basal water permeability, leading to increased diuresis and NDI, although this appears to be uncommon 124 …”

“…Hypoxic encephalopathy or severe ischaemia can lead to diminished AVP release from the SON 95 . Beyond this mechanism, a recent in vitro study has shown that Lgals3 , a microglial activation‐related gene, plays an important role in the elimination of AVP neurons by inducing phagocytic activity of the microglia after hypothalamic injury, and thus may also be implicated in AVP deficiency 96 …”