Reply to the Letter to the Editor from Yanyu Zhang: ‘Considering a renal origin of endocrine hypertension in ASIC1a‐deficient mice’

We thank Dr Zhang for the thoughtful comments and interest in our recent study examining the role of acid-sensing ion channel 1a (ASIC1a) in age-related endocrine hypertension in male mice. We agree with the main point raised in the Letter to the Editor that progression of the pathology may be partly driven by persistent peripheral signals, which aligns with the multisystem nature of hypertension. While ASICs have historically been studied in the nervous system due to their prominent and widespread expression there, this perspective emphasizes the importance of considering less well-known roles for ASIC1a in other tissues. Hypertension is inherently a multisystem disorder, and integration of central and peripheral signals is probably critical to the endocrine and cardiovascular phenotype we observed. Dr Zhang proposes that a persistent impairment in renal ion handling is the initial event in global Asic1a knockout (Asic1a−/−) mice, with hypothalamic stress response occurring secondarily due to systemic homeostatic disturbance. This is a likely possibility that we have also considered extensively and agree merits further investigation. Supporting this view, the Human Protein Atlas shows that Asic1 transcripts are present in renal tubular segments, including the proximal tubule epithelium and collecting duct principal and intercalated cells, which are crucial regions for acid–base and electrolyte regulation (Uhlén et al. , 2015). Consistent with a renal contribution, we observe a systemic acid–base disturbance in both male and female Asic1a−/− mice. Specifically, reductions in circulating HCO3− together with decreased P C O 2 {P₂{{{O}₂}}} align with metabolic acidosis with respiratory compensation (Garcia et al. , 2026). This metabolic acidosis profile is further supported by our ongoing metabolomic analysis of these animals and could potentially lead to hypokalaemia. Importantly, however, hypokalaemia and reduced urine osmolality are observed only in male Asic1a−/− mice, despite the presence of similar acid–base disturbances in females. As Dr Zhang suggests in his letter, this divergence may reflect sex-specific regulatory mechanisms that influence electrolyte balance, such as oestrogen inhibition of epithelial sodium channel (ENaC) expression and activity (Nasci et al. , 2025). ASIC and ENaC belong to the same ion channel family and have also been shown to form functional hybrid channels (Kapoor et al. , 2011; Trac et al. , 2017). It is possible that ASIC1a alone, or in conjunction with ENaC, could influence renal sodium and potassium transport. However, if this were the predominant mechanism leading to hypokalaemia, one might predict that loss of ASIC1a or ASIC1a/ENaC would reduce sodium reabsorption and, in turn, potassium secretion, rather than the hypertensive phenotype observed in our model. Future studies will be important to determine whether ASIC1a directly modulates renal acid–base and/or electrolyte regulation. Our focus on hypothalamic signaling was guided by the identification of early changes in male, but not in female, Asic1a−/− mice that could contribute to the development of the hypertensive phenotype. In particular, we observed an early elevation in corticosterone that was not present in females, suggesting a potential endocrine mechanism. This interpretation was further supported by transcriptomic data indicating early alterations in hypothalamic stress circuitry in male Asic1a−/− mice (Garcia et al. , 2026). Because corticosterone binds mineralocorticoid receptors with an affinity comparable to that of aldosterone (Gomez-Sanchez et al. , 2017), elevated corticosterone could exert aldosterone-like effects on sodium retention, potassium balance (hypokalaemia) and blood pressure regulation. This link between altered stress–axis activity, hypokalaemia and cardiovascular changes provides a plausible mechanism contributing to the observed sexual dimorphism. However, because sex differences in acid–base handling and the temporal relationship between acid–base disturbances and endocrine changes remain unclear, it is also possible that systemic metabolic acidosis contributes to the activation of the hypothalamic stress response in males, while females may be more capable of compensating for acid–base disturbances. As noted by Dr Zhang, alterations in potassium balance can influence adrenal steroidogenesis independent of hypothalamic signaling. However, elevations in extracellular potassium are classically recognized as a direct, non-RAAS (renin–angiotensin–aldosterone system) stimulus for aldosterone secretion (Hattangady et al. , 2012). The presence of hypokalaemia in male Asic1a−/− mice, therefore, suggests that additional regulatory mechanisms probably contribute to the observed endocrine phenotype, indicating that the underlying physiology may be more complex than a purely renal or adrenal initiating event. As Dr Zhang suggested, these possibilities highlight the importance of defining the temporal sequence of renal, endocrine and central changes in both sexes in this model. In summary, we appreciate Dr Zhang's engagement with our study and the alternative renal-centred framework proposed in their letter. Peripheral signals, including those arising from the kidney, probably contribute to the pathophysiology observed in Asic1a−/− mice. Our findings suggest that the phenotype probably arises from interactions between central stress circuitry and multiple peripheral systems. Although cell-type-specific or inducible approaches may ultimately help dissect the contribution of individual tissues, the highly integrated nature of this physiology suggests that no single manipulation is likely to fully recapitulate the mechanisms driving the phenotype. Clarifying the temporal sequence and relative contributions of renal, endocrine and central mechanisms will therefore be an important direction for future work. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests are declared. N. L. J.: Conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. Nikki L. Jernigan has received funding from National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI): HL111084; American Heart Association (AHA): 18TPA34110281.