Chronic Metabolic Acidosis Elicits Hypertension via Upregulation of Intrarenal Angiotensin II and Induction of Oxidative Stress

Abstract

Chronic metabolic acidosis (CMA) can be a consequence of persistent hypertension but could potentially play a role in invoking hypertension. Currently, there is a scarcity of studies examining the outcome of induced chronic acidosis on blood pressure regulation. This study investigates CMA as a cause of hypertension. Chronic acidosis was induced in Sprague Dawley rats (100–150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4Cl) in tap water for 8 weeks. To determine whether the rats were acidotic, blood pH was measured, while blood pressure (BP) was monitored by tail-cuff plethysmography weekly. Rats were divided into five groups: control, CMA, CMA ± spironolactone, captopril, and tempol. Serum sodium and potassium; renal interstitial fluid (for Angiotensin II concentration); and kidney proximal tubules (for Na+/K+ ATPase- α1 concentration) were analyzed. Reactive oxygen species (ROS) were detected in renal cortical homogenates using electron paramagnetic resonance (EPR). In the CMA rats, a sustained elevation in mean arterial pressure (MAP) associated with a significant decrease in blood pH was observed compared to that of control over the 8 weeks. A significant decrease in MAP was observed in acidotic rats treated with captopril/tempol, whereas spironolactone treatment caused no decrease in MAP as compared to that of the CMA group. The interstitial angiotensin II was increased in the CMA group but decreased in the CMA with captopril and tempol groups. In addition, the urinary sodium was decreased, and the serum sodium levels increased significantly in the CMA groups as compared to that of control. However, the acidotic groups with captopril and tempol showed reduced levels of serum sodium and an elevation in urinary sodium as compared to that of the CMA group. In addition, there was a significant increase in plasma renin and no change in plasma aldosterone in the CMA group with no significant differences in plasma renin or aldosterone observed during spironolactone, captopril, or tempol treatments. The increased expression of Na+/K+ ATPase-α1 in the CMA group suggests that active transport of Na+ to the blood could be causative of the observed hypertension. Furthermore, the EPR analysis confirmed an elevation in superoxide (O2-) radical levels in the CMA group, but the tempol/captopril treated acidotic groups showed less (O2-) compared to that of either the CMA group or control. Taken together, our data suggest that induction of CMA could potentially be causative of hypertension, while the mechanisms underlying the increased BP could be through the activation of intrarenal Ang II and induction of oxidative stress.

Association of Plant-Based Protein Intake with Cognitive Function in Adults with CKD

“…Metabolic acidosis is associated with outcomes such as vascular dysfunction, inflammation, oxidative stress, as well as CKD progression and mortality. [22][23][24] All these impairments of cardiovascular and cerebrovascular function may contribute to cognitive impairment and decline. In previous work, metabolic acidosis has been associated with cognitive impairment in 2853 older hypertensive participants with and without CKD.…”

N-Acetyl-L-Cysteine Protects Organ Function After Hemorrhagic Shock Combined With Seawater Immersion in Rats by Correcting Coagulopathy and Acidosis

“…When the rats were in an anoxic state, anaerobic fermentation in tissue cells were thus enhanced, causing the accumulation of acid products ( Gupte et al, 2016 ). Some studies demonstrated that oxidative stress was a result of hypoxia and acidosis but whether improved oxidative stress could correct acidosis was unclear ( Aryal et al, 2020 ). Our results showed that LR solution with addition of NAC (30 mg/kg) almost recovered the PH back to the normal level, which was better than LR solution or HES solution used alone.…”

Associations of Metabolic Syndrome and Abdominal Obesity with Anion Gap Metabolic Acidosis among US Adults

“…Truly reduced pH within tissue, for example within muscle (40), would certainly urge greater consideration of the role of MA in cardiometabolic disease pathophysiology. Acid retention causes kidney function decline (7,8), is implicated in hypertension (45,46), and associates with greater mortality (3). If acid were retained in this patient group, both supplemental and dietary alkali might be studied as preventive measures.…”