Sodium pump ligands in blood pressure regulation and profibrotic signaling in hypertension, chronic kidney disease and aging in males and females

National Institute On Aging

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Abstract

To achieve the above goal, we have performed the following experiment in a cross-sectional collaborative clinical study. The markers of oxidative stress, inflammation, fibrosis and neurodegeneration, and cognitive function, along with the physiological and clinical CKD and CVD parameters, were estimated and analyzed in CKD patients and healthy controls, equally represented by both sexes. CVD, CKD and mini-mental state examination (MMSE) to estimate cognitive function, plasma BNP, a marker of CVD, marinobufagenin (MBG), a profibrotic marker, pTau and A42/40 ratio, the markers of neurodegeneration, were assessed in all patients. We elucidated the sex-specific associations among these factors through linear regression and path analyses. CKD patients have higher blood pressure vs. controls, and men with CKD exhibited decline in cardiac function vs. sex- and age-matching controls. Both men and women with CKD had lower MMSE scores vs. controls, although cognitive performance in CKD-women was significantly better than CKD-men. Nevertheless, the path analysis revealed a direct association of the plasma pTau and A42/40 ratio with MMSE scores in women only. BNP, pTau and MBG were associated with short-term memory, a part of MMSE assessment, also in women only as it was demonstrated by path analysis. Our findings will broaden the current understanding and clinical consequences of the pathophysiological interactions between kidney and cardiovascular damage with brain function in a sex-dependent manner that may undoubtedly prompts early diagnosis and innovative pharmacological interventions. In summary, the findings of the present study highlight the importance of a sex-based evaluation of CKD-mediated cognitive dysfunction that connects the kidney-heart-brain axis. We demonstrated that CKD with CVD comorbidity is significantly associated with CI that follows a sex-specific pattern. CKD was associated with similar magnitude of changes in the levels of the fluid biomarkers of CKD, CVD, fibrosis and neurodegeneration in men and women. Nevertheless, our findings show that CVD is a major contributor to CKD-mediated CI in men, in which a dysregulation in fibrosis and oxidative stress biomarkers potentiates neurodegeneration and cognitive dysfunction. Although women with CKD exhibited higher cognitive performance in MMSE than men with CKD, the association of pTau and Aβ42/40 with MMSE score was observed exclusively in women. The study establishes a detailed sex-based correlation analysis of physiological and clinical parameters relevant to CKD and CVD pathogenesis with neurodegenerative markers. Kidney-heart-brain axis in CKD displays sex-dependent crosstalk between the parameters that arrange this axis. The results draw consideration to the sex disparity that recommends personalized care for CKD patients with CVD pathology to manage the progression of CI. This will help to formulate a sex-specific care that may include interventions for lifestyle modifications, hormonal therapies, etc., to enhance the quality of life. The observed discrepancy between men and women concerning CKD-mediated CI should be addressed in detail for early diagnosis and appropriate disease management in clinical settings.