Reduction of renal triglyceride accumulation: Effects on proximal tubule Na+/H+ exchange and urinary acidification

I. Alexandru Bobulescu, Michele Dubree, Jianning Zhang, Paul McLeroy, Orson W. Moe

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


One main pathophysiological mechanism underlying the increased risk for uric acid nephrolithiasis in humans with the metabolic syndrome is the excretion of unduly acidic urine, in part because of reduced excretion of the main urinary buffer, ammonium. The Zucker diabetic fatty (ZDF) rat, an established rodent model of the metabolic syndrome, has similar urinary abnormalities, attributed in part to lower expression and activity of the principal mediator of proximal tubule ammonium excretion, brush-border membrane Na+/H + exchanger 3 (NHE3). These defects are associated with renal tubular steatosis in ZDF rats, but the causal relationship between renal steatosis and defective urinary acidification has not been investigated in vivo. We hypothesized that reduction of renal steatosis would commensurately normalize urinary acidification parameters. We treated ZDF rats with thiazolidinediones to reduce nonadipose tissue steatosis. Four weeks of treatment reduced renal triglyceride accumulation and restored urinary acidification parameters in ZDF rats to levels comparable to their lean littermates; urinary acidification was not affected by treatment in lean rats. To further document the direct effects of fat, we showed that functional abnormalities induced by fat loading in a cell culture model of proximal tubule steatosis and lipotoxicity can be reversed by fat removal but not by thiazolidinediones alone. Together, these findings support the causative role of renal steatosis in the pathogenesis of urinary acidification defects, demonstrate reversibility upon lipid removal, and highlight a potential therapeutic strategy for renal abnormalities in the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)F1419-F1426
JournalAmerican Journal of Physiology - Renal Physiology
Issue number5
StatePublished - Nov 2009


  • Ammonium
  • Metabolic syndrome
  • Na/H exchanger 3
  • Renal lipotoxicity
  • Uric acid nephrolithiasis

ASJC Scopus subject areas

  • Physiology
  • Urology


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