Table 2.

Effects of the angiotensin II response to metabolic acidosis

ModelMeasurementsObservationsConclusionsReferences
Rodent model, exposure to NH4ClRAAS components gene expression, including angiotensinogen, ACE, AT1R and AT2RAngiotensinogen, ACE, AT1R, and AT2R were significantly increased (all P<0.05) after 1 wk of exposure to NH4Cl compared with control and NaCl-treated groups. Sustained AT1R expression was found in the NH4Cl group after 8 wkSustained expression of intrarenal AT1R is consistent with an increase in kidney angiotensin II accompanying acidosis49,105
Subtotal nephrectomy in ratsIntrakidney angiotensin II, angiotensin II receptor, intrakidney acid loadIncreased acid load and increased intrakidney levels of angiotensin II detected. Angiotensin II receptor antagonism (with valsartan) reduced distal nephron acidification to sham-operated control animal levels. Dietary alkali reduced intrakidney levels of angiotensin II and reduced distal nephron acidification (all P<0.05)Subtotal nephrectomy increased kidney levels of angiotensin II mediated by acid retention associated with GFR reduction39,40,112
Kidney physiology studiesMeasurement of the effects of angiotensin II on glomerular filtration barrier and selectivityAngiotensin II decreased the synthesis of negatively-charged proteoglycans and suppressed nephrin transcription, a transmembrane protein that maintains the podocyte structure. Angiotensin II–mediated suppression of nephrin resulted in podocyte apoptosis and overall reduction of GFR (all P values <0.05)Angiotensin II exhibits direct effects on the integrity of the glomerular filtration barrier108,123125
Animal transfection studiesAnimal transfection with viral vectors that overexpress renin and angiotensinogen in rat glomeruliSeven days after transfection, extracellular matrix was expanded in rats with glomerular renin and angiotensinogen overexpression, leading to fibrosis and kidney scarring. Transfected animals that received 4 wk of irbesartan treatment had significantly lower levels of angiotensin II and tubulointerstitial fibrosis (P<0.005) compared with control animalsAngiotensin II is directly involved in kidney fibrosis; fibrosis is a contributing factor in progressive GFR decline in CKD121,126
Acidemia induced in volunteers with NH4ClMeasurements of plasma aldosterone concentration, urinary aldosterone secretion; cortisol, corticosterone, deoxycorticosterone, plasma renin, plasma K+, AT1RPlasma aldosterone concentration and urinary aldosterone secretion was increased, without significant changes in cortisol, corticosterone, deoxycorticosterone, plasma renin activity, or serum K+. Indicates that plasma H+ concentration is a direct and separate regulator of aldosterone secretion, sensitive to net acid load in the body. AT1R blockade by losartan exacerbated the induced acidosis by blocking distal tubular acidification in response to the acid challenge (all P values <0.05)Acidemia induced in human volunteers with NH4Cl increased RAAS activity, including angiotensin II and AT1R127129
Effect of dietary alkali on net acid excretion, ET-1, and aldosterone in subjects with CKD stage 2Plasma ET-1, aldosterone, NAE in subjects with CKD stage 2Baseline plasma ET-1 and aldosterone concentrations were each higher in the patients with CKD 2 than in normal control subjects (P<0.05). An oral bolus of NaHCO3 reduced urine NAE less in those with CKD 2 than in normal subjects, consistent with greater acid retention in the subjects with CKD 2 (P<0.05). Thirty days of oral NaHCO3 reduced acid retention in subjects with CKD 2, but not in normal subjects, and reduced plasma ET-1 and aldosterone in both groups but to levels that remained higher in the patients with CKD 2 (P<0.05)Dietary alkali can reduce acid retained in patients with CKD stage 2 who are eubicarbonatemic, possibly through reduction of ET-1 and aldosterone38
Effect of dietary intervention on UAGT excretionUAGT excretionPatients with reduced GFR and metabolic acidosis had increased urine excretion of angiotensinogen that was decreased after dietary acid reduction with NaHCO3 or base-producing fruits and vegetables (P<0.05)UAGT reflects kidney levels of angiotensin II; dietary intervention with alkali (fruits and vegetables) can decrease UAGT and kidney angiotensin II levels61,109,111
  • NH4Cl, ammonium chloride; ACE, angiotensin-converting enzyme; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; NaCl, sodium chloride; NAE, net acid excretion; UAGT, urinary angiotensinogen.