Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation

Hanning You, Ting Gao, Timothy K. Cooper, Sidney M. Morris, Alaa S. Awad

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate L-arginine. Lack of L-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that L-arginine or L-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without L-arginine (1.5%, 6.05 g·kg_1·day_1) or L-citrulline (1.66%, 5.73 g·kg_1·day_1) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-α and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, L-arginine or L-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic L-arginine or L-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)F1292-F1301
JournalAmerican Journal of Physiology - Renal Physiology
Issue number11
StatePublished - Dec 1 2014

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology


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