The role of the renal ammonia transporter Rhcg in metabolic responses to dietary protein

J Am Soc Nephrol. 2014 Sep;25(9):2040-52. doi: 10.1681/ASN.2013050466. Epub 2014 Mar 20.


High dietary protein imposes a metabolic acid load requiring excretion and buffering by the kidney. Impaired acid excretion in CKD, with potential metabolic acidosis, may contribute to the progression of CKD. Here, we investigated the renal adaptive response of acid excretory pathways in mice to high-protein diets containing normal or low amounts of acid-producing sulfur amino acids (SAA) and examined how this adaption requires the RhCG ammonia transporter. Diets rich in SAA stimulated expression of enzymes and transporters involved in mediating NH4 (+) reabsorption in the thick ascending limb of the loop of Henle. The SAA-rich diet increased diuresis paralleled by downregulation of aquaporin-2 (AQP2) water channels. The absence of Rhcg transiently reduced NH4 (+) excretion, stimulated the ammoniagenic pathway more strongly, and further enhanced diuresis by exacerbating the downregulation of the Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and AQP2, with less phosphorylation of AQP2 at serine 256. The high protein acid load affected bone turnover, as indicated by higher Ca(2+) and deoxypyridinoline excretion, phenomena exaggerated in the absence of Rhcg. In animals receiving a high-protein diet with low SAA content, the kidney excreted alkaline urine, with low levels of NH4 (+) and no change in bone metabolism. Thus, the acid load associated with high-protein diets causes a concerted response of various nephron segments to excrete acid, mostly in the form of NH4 (+), that requires Rhcg. Furthermore, bone metabolism is altered by a high-protein acidogenic diet, presumably to buffer the acid load.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Sulfur / administration & dosage
  • Ammonia / metabolism*
  • Animals
  • Aquaporin 2 / metabolism
  • Bone Resorption / etiology
  • Bone Resorption / metabolism
  • Bone and Bones / metabolism
  • Caseins / administration & dosage
  • Caseins / adverse effects
  • Caseins / chemistry
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Dietary Proteins / administration & dosage*
  • Dietary Proteins / adverse effects
  • Dietary Proteins / chemistry
  • Diuresis
  • Hydrogen-Ion Concentration
  • Kidney / metabolism*
  • Kidney Medulla / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Solute Carrier Family 12, Member 1 / metabolism
  • Soybean Proteins / administration & dosage
  • Soybean Proteins / chemistry
  • Urine / chemistry


  • Amino Acids, Sulfur
  • Aqp2 protein, mouse
  • Aquaporin 2
  • Caseins
  • Cation Transport Proteins
  • Dietary Proteins
  • Membrane Glycoproteins
  • Rhcg protein, mouse
  • Slc12a1 protein, mouse
  • Solute Carrier Family 12, Member 1
  • Soybean Proteins
  • Ammonia