Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention

Abstract

Patients with a moderately reduced glomerular filtration rate (GFR) typically have no metabolic acidosis and a urine net acid excretion comparable to those with normal GFR, supporting greater per nephron acidification with moderately reduced GFR. We modeled such patients using rats with a surgical reduction of 2/3 kidney mass, yielding animals with reduced GFR without metabolic acidosis. We then tested the hypothesis that reduction of nephron mass augments distal nephron acidification in remnant nephrons mediated by increased angiotensin II activity, and that the latter is induced by underlying acid retention. Nephron mass reduction yielded lower GFR than controls (sham operation), higher acid retention (measured by microdialysis of kidney cortex), higher distal nephron acidification, and higher plasma and kidney levels of angiotensin II, but plasma total CO(2) and urine net acid excretion were not different. Angiotensin II receptor antagonism reduced distal nephron acidification to levels similar to control. Dietary alkali that lowered acid retention to that of control also reduced plasma and kidney levels of angiotensin II and reduced distal nephron acidification to control. Angiotensin II receptor antagonism with dietary alkali had no significant added effect on distal nephron acidification. Thus, nephron reduction that moderately reduced GFR with no metabolic acidosis is characterized by increased angiotensin II activity. This mediates increased distal nephron acidification and is induced by acid retention.

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

“…Although some observations pointed to a beneficial effect of acidosis in experimental renal disease in rodents, 28,32,33 the bulk of observations indicate that alkali treatment has beneficial and acidosis exacerbatory effects in experimental CKD. [34][35][36][37] Moreover, clinical studies in humans demonstrate that acidosis accelerates and alkali treatment retards the progression of CKD. 34,39,[74][75][76] Along those lines, decreased bicarbonate concentrations are associated with decline of eGFR in community-living older persons.…”

“…38 Moreover, administration of alkali retards the progression of CKD in rodents. [34][35][36][37] In humans with CKD, acidosis is associated with worse kidney function, whereas the administration of bicarbonate, as shown in several studies, is associated with the slowing of progressive kidney disease. 37,39 Acidosis can be induced by dietary NH 4 Cl.…”

“…[34][35][36][37] In humans with CKD, acidosis is associated with worse kidney function, whereas the administration of bicarbonate, as shown in several studies, is associated with the slowing of progressive kidney disease. 37,39 Acidosis can be induced by dietary NH 4 Cl. 40 42 In acidic compartments, NH 3 binds H + and is thus trapped as NH 4 + .…”

“…On the one hand, metabolic acidosis has been reported to slow the progression of renal disease in rats. 28,32,33 On the other hand, acidosis has been shown to worsen experimental CKD, [34][35][36][37] especially cystic kidney disease. 38 Moreover, administration of alkali retards the progression of CKD in rodents.…”

Autophagic Clearance of Mitochondria in the Kidney Copes with Metabolic Acidosis

“…In previous studies, MA was found to activate a series of regulatory mechanisms to compensate for disordered acid-base balance, including complement activation, 30 endothelin production, and activation of the renin-angiotensin system. [31][32][33] This subsequently induced additional kidney damage. However, in contrast with clinical consequences such as the development of a catabolic state, 34 development or exacerbation of bone disease, 35 and deterioration of kidney function, 36 the decisive mechanism by which MA induces cellular dysfunction was largely unknown.…”