Decrease in tetrahydrobiopterin as a possible cause of nephropathy in type II diabetic rats

Kidney Int. 2006 Aug;70(3):471-6. doi: 10.1038/ Epub 2006 Jun 14.


A decrease in renal synthesis of nitric oxide (NO) in the progression of diabetic nephropathy has been documented. As (6R)-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor of NO synthase, we investigated whether BH4 deficiency is involved in the pathogenesis of nephropathy. Ten-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as a type II diabetic model, and Long-Evans Tokushima Otsuka (LETO) rats as the healthy controls. OLETF rats were orally treated with BH4 (10 mg/kg daily) or with water from 10 to 61 weeks of age. In another experiment, OLETF rats were treated orally with a calcium channel blocker, benidipine (5 mg/kg daily), or with 0.3% carboxymethyl cellulose (nontreated) from 10 to 52 weeks of age. Proteinuria was observed periodically, and at the end of the study, BH4 level and GTP cyclohydrolase I (GTPCH) activity in the kidney were measured. Proteinuria was observed at 13 weeks of age in the OLETF rats, and deteriorated until 61 weeks of age. Supplemental BH4 reduced the proteinuria. At 52 weeks of age, GTPCH activity and the BH4 level were decreased in the plasma and kidneys of OLETF rats, whereas they were significantly higher in the benidipine group than in the nontreated group. Proteinuria was milder in the benidipine group than in the nontreated group, without a concomitant decrease in blood pressure. Histologically observed glomerulosclerosis was mild in the BH4 and benidipine groups. In type II diabetic rats, renal BH4 is considered to play a crucial role in the pathogenesis of diabetic nephropathy. Benidipine was found to preserve BH4 levels, suggesting therapeutic renoprotective effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopterin / analogs & derivatives*
  • Biopterin / blood
  • Biopterin / deficiency
  • Biopterin / pharmacology
  • Blood Glucose
  • Blood Pressure
  • Body Weight
  • Calcium Channel Blockers / pharmacology
  • Creatinine / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / etiology*
  • Diabetic Nephropathies / metabolism*
  • Dihydropyridines / pharmacology
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Nitric Oxide / metabolism
  • Proteinuria / drug therapy
  • Proteinuria / etiology
  • Proteinuria / metabolism
  • Rats
  • Rats, Inbred OLETF
  • Rats, Long-Evans


  • Blood Glucose
  • Calcium Channel Blockers
  • Dihydropyridines
  • Biopterin
  • Nitric Oxide
  • benidipine
  • Creatinine
  • sapropterin