Renal Adaptive Changes in Response to Chronic Metabolic or Respiratory Acidosis: Regulation of Expression of Acid‐base Transporters and Enzymes
Authors: Nakhoul Nazih L , Hering‐Smith Kathleen , Hamm L. Lee , Abdulnour‐Nakhoul Solange 
Published: June 2021

Kidneys excrete acid loads mainly by generating and excreting total ammonia (NH3plus NH4+) and to a lesser extent titratable acids (TA). Urinary excretion of NH3/NH4+ and TAincreases significantly in acidosis. We made the assumption that this augmented urinary acid excretion (NH3/NH4+and TA) will differ depending on the type of acid‐load. To test this hypothesis, we conducted in‐vivo experiments on mice to measure urinary NH3/NH4+and TA under metabolic or respiratory acid loads and investigated expression of carbonic anhydrase and acid‐base transporters by Western analysis.

We induced metabolic acidosis in 2 groups of mice: one group received an acid diet (AD) supplemented with 0.4N HCl (at 1mg/g of chow); a second group received drinking water fortified with NH4Cl (0.28M) and 1% sucrose (NH4+‐W); a control group received normal diet (ND). Our data showed that urinary NH4+(u‐NH4+) increased gradually in mice on AD or NH4–W diet compared to control (ND) and the increase in u‐NH4+was proportionally higher than that of TA. Unexpectedly, expression of the NH3/NH4+transporters, Rhbg and Rhcg, in both groups of acid‐loaded mice was not significantly different compared to mice on ND. An interesting finding, however, was that expression of CA‐IV was reduced in both acidosis groups. In mice on AD, RNAseq data showed that carbonic anhydrase‐II (CA‐II) was upregulated whereas pendrin (a Cl‐HCO3−exchanger) expression was downregulated.

We induced chronic respiratory acidosis by placing mice for 3 days in special chambers where breathing gas mixtures were 8% CO2(balance 21% O2& 71% N2). A control group breathed normal air. There were no significant changes in urinary excretion of TA in both hypercapnic or control groups. However, urinary NH4+in hypercapnic mice increased significantly after 24 hours and continued to gradually increase in days 2 and 3. In control mice, there was a small increase in urinary NH4+excretion in day 1 (p < 0.05), probably caused by housing distress in metabolic cages, but leveled off in days 2 and 3. Western analysis showed that hypercapnia induced a marked increase in expression of Rhbg but only a moderate increase of Rhcg. Chronic hypercapnia increased expression of CA‐IV significantly but decreased expression of pendrin.

In summary, we demonstrated that renal response to acidosis varies with the type of acid load. High CO2 acidosis downregulated pendrin even though plasma HCO3−is high. In metabolic acidosis, the increase in urinary NH4+is likely caused by increased ammoniagenesis, whereas upregulation of NH3/NH4+transporters is more evident in respiratory than in metabolic acidosis. These data show a link among chronic hypercapnia, NH4+excretion and expression of the NH3/NH4+transporters, Rhbg and Rhcg. These studies are important to understand the renal mechanisms of correcting respiratory and metabolic acidosis.

Support or Funding Information

U54 GM104940 from NIH, VA Merit grant, NIH‐RO1, Carol Lavin Bernick grant and Tulane Bridge grant

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.