Effect of renal tubule-specific knockdown of the Na+/h+ exchanger NHE3 in akita diabetic mice

Akira Onishi, Yiling Fu, Manjula Darshi, Maria Crespo-Masip, Winnie Huang, Panai Song, Rohit Patel, Young Chul Kim, Josselin Nespoux, Brent Freeman, Manoocher Soleimani, Scott Thomson, Kumar Sharma, Volker Vallon

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Na+/H+ exchanger isoform 3 (NHE3) contributes to Na+/bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knockdown [Pax8-Cre; NHE3-knockout (KO) mice] were generated. NHE3-KO mice had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate, and glucose (phos-phoenolpyruvate carboxykinase) in proximal tubules and H+ and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in nondiabetic and diabetic NHE3-KO versus wild-type mice but was associated with renal upregulation of proinflammatory markers. Higher renal phosphoenolpyruvate carboxykinase expression in NHE3-KO mice was associated with lower Na+-glucose cotransporter (SGLT)2 and higher SGLT1 expression, indicating a downward tubular shift in Na+ and glucose reabsorption. NHE3-KO was associated with lesser kidney weight and glomerular filtration rate (GFR) independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing kidney weight and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type mice; stronger SGLT1 engagement could have affected kidney weight and GFR responses. Chronic kidney disease in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids and the tricarboxylic acid cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in nondiabetic NHE3-KO mice, possibly reflecting branched-chain amino acids use for ammoniagenesis and tricarboxylic acid cycle upregulation to support formation of ammonia, bicarbonate, and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.

Original languageEnglish (US)
Pages (from-to)F419-F434
JournalAmerican Journal of Physiology - Renal Physiology
Issue number2
StatePublished - Aug 2019


  • Albuminuria
  • Diabetes mellitus
  • Diabetic nephropathy
  • Hyperfiltration
  • Na-glucose cotransporter 2
  • Proximal tubule
  • Tubular growth

ASJC Scopus subject areas

  • Urology
  • Physiology


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