Renin–Angiotensin–Aldosterone System Imbalance and Altered Aquaporin Activity: A New Perspective for COVID-19-Associated Xerostomia

We read with interest the article by Saniasiaya ¹ highlighting the importance of recognizing xerostomia as a common symptomatology of COVID-19. We concur with the authors’ opinion, especially considering the fact that in 60% of cases of xerostomia is one of the earliest presentations, ² mostly reported concomitantly with gustatory and olfactory dysfunction, ³ and that salivary gland viral burden correlates with COVID-19 symptoms, including taste loss. ⁴ Thus, it is important to delineate the mechanisms of xerostomia in COVID-19, as this could shed light on the early etiopathology of COVID-19 pneumonia. Recently, renin–angiotensin–aldosterone system (RAAS) imbalance involving angiotensin converting enzyme (ACE) 2 (ACE2) downregulation, ACE upregulation, and angiotensin II (Ang-II) overactivity–mediated vasoconstrictive, pro-inflammatory, pro-thrombotic, and pro-fibrotic signaling cascades have been implicated in COVID-19 pathophysiology. ⁵ We herein further postulates a plausible role of ACE-Ang-II-AT1R overactivity in COVID-19-associated xerostomia.

Recently, SARS-CoV-2 tropism is identified for ACE2/TMPRSS2-expressing acini, duct epithelial cells, and blood vessels in minor as well as major salivary glands. ⁴ Following, SARS-CoV-2 infection of the salivary glands, downregulation of ACE2, and upregulation of ACE-Ang-II-AT1R activity may develop in the salivary glands and can possibly reduce the salivary flow by the following mechanisms:

 Vasoconstriction: McKinley et al studied the effect of a physiological dose range Ang-II infusion on parotid saliva secretion in conscious sheep and demonstrated a dose-dependent reduction in parotid saliva secretion. ⁶ Infusion of Ang-II into the carotid artery ipsilateral to the parotid gland under study caused a greater reduction in saliva secretion rate than an equivalent infusion of Ang-II into the contralateral carotid artery. ⁶ This result suggests a direct effect of Ang-II at the parotid, possibly by its vasoconstrictor action or by altering water and electrolyte transport by the gland. Notably, saliva flow increased after intravenous infusion of the Ang-II antagonist, saralasin. ⁶ Further, in healthy volunteers, captopril enhanced salivary flow rate without altering the salivary composition. ⁷

 Inflammation: Ang-II may be a mediator of SARS-CoV-2-induced sialadenitis as it can synergistically potentiates tumour necrosis factor alpha, interleukin (IL)-6 and IL-1β activity, and nuclear factor kappa B (NF-κB) pathways.

 Endothelial dysfunction: Upregulation of ACE-Ang-II-AT1R activity can produce endothelial dysfunction resulting in microthrombotic occlusion of vessels in the salivary glands. In fact, a few clinico-histopathology reports associated oral lesions in patients with COVID-19 with microvascular thrombi. ⁸

 Altered Aquaporin 5 expression: In human salivary glands, AQP5 (a rate-limiting water channel protein in respiratory mucosa) has been localized to the apical membranes of acinar cells, where it stimulates the outflow of water into the acinar lumen. ⁹ Although the underlying molecular and physiological alterations linking reduced AQP5 expression to increased RAAS activity remain to be studied, ⁹ AA-genotypes of the AQP5-1364A/C are associated with greater AQP5 expression, high RAAS activity, increased pulmonary inflammation, and increased risk of kidney injury in acute respiratory distress syndrome (ARDS). ¹⁰ Contrary, lower AQP5 expression increased survival in ARDS and sepsis. Pro-inflammatory NF-κB pathways suppress AQP5 expression as an attempt to provide protective benefit against inflammation. ¹⁰ Tumour necrosis factor alpha also reduces fluid secretion from salivary acinar cells by suppressing AQP5 expression. ¹¹ Further, a proteomic analysis in spontaneous hypertensive rats revealed an impaired Ca²⁺/AQP5 pathway in the submandibular gland, linking hyposalivation with hypertension and reduced AQP5 activity. ¹² Based on the decreased AQP5 expression hypothesis, like anosmia and dysgeusia, xerostomia appears to link with less severe COVID-19 disease.

Overall, similar to other proposed mechanisms for COVID-19-associated xerostomia, ^2,3 the role of ACE/ACE2 imbalance in xerostomia warrants further research.