Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD).

Abstract

AIMS:

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been reported to be a novel marker for the progression of chronic kidney disease (CKD). We have recently found that accumulation of ADMA could trigger peritubular capillary loss, thus contributing to tubulointerstitial ischemia and fibrosis in a rat model of CKD. However, effects of ADMA on glomerular capillary loss and sclerosis remain to be elucidated.

MAIN METHODS:

In this study, we investigated whether lowering of ADMA by overexpression of dimethylarginine dimethylaminohydrolase (DDAH), a main enzyme that degrades ADMA, could ameliorate glomerular capillary loss and sclerosis in a rat model of CKD. Four weeks after 5/6 subtotal nephrectomy (Nx), animals were given tail vein injections with recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ), or orally administered with 20 mg/kg/day of hydralazine (Hyz) which served as a blood pressure control model.

KEY FINDINGS:

Plasma levels of ADMA were associated with decreased number of glomerular capillaries as well as severity of glomerular sclerosis in Nx-rats. These glomerular changes progressed in Adv-LZ- or Hyz-treated Nx-rats, while they were ameliorated by the treatment with DDAH overexpression.

SIGNIFICANCE:

Our present data suggest that ADMA may be involved in glomerular capillary loss and sclerosis, thus contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.

• Authors: Seiji Ueda, Sho-ichi Yamagishi, Yuriko Matsumoto, Yusuke Kaida, Ayako Fujimi-Hayashida, Kiyomi Koike, Hideharu Tanaka, Kei Fukami, Seiya Okuda
• Journal: Life sciences (Life Sci) Vol. 84 Issue 23-24 Pg. 853-6 (Jun 05 2009) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 19351540 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• N,N-dimethylarginine
• Arginine
• Amidohydrolases
• dimethylargininase

Topics

• Amidohydrolases (biosynthesis)
• Animals
• Arginine (analogs & derivatives, physiology)
• Capillaries (metabolism, pathology)
• Disease Models, Animal
• Glomerulosclerosis, Focal Segmental (metabolism, pathology)
• Humans
• Kidney Failure, Chronic (metabolism, pathology)
• Kidney Glomerulus (blood supply, metabolism, pathology)
• Rats