Apocynin attenuates tubular apoptosis and tubulointerstitial fibrosis in transgenic mice independent of hypertension.

Abstract

Angiotensin II stimulates the formation of reactive oxygen species by increased NADPH oxidase activity, which contributes to proapoptotic and profibrotic mechanisms critical in renal injury. Here we determine if apocynin, an inhibitor of NADPH oxidase, interferes with the action of the intrarenal renin-angiotensin system to minimize the progression of renal disease. Transgenic mice that overexpress rat angiotensinogen in their proximal tubule cells were given either apocynin, perindopril, or hydralazine while untreated or apocynin-treated non-transgenic littermates served as controls. Untreated transgenic mice had significant elevations of their systolic blood pressure, albuminuria, reactive oxygen species production, NADPH oxidase activity, tubular apoptosis, active caspase-3, Bax, transforming growth factor-beta1, plasminogen activator inhibitor-1, extracellular matrix proteins, collagen type IV, and phosphorylated p47phox expression compared to untreated non-transgenic mice. Apocynin and perindopril blunted these changes; however, apocynin had no effect on the systolic blood pressure whereas hydralazine prevented hypertension and tubulointerstitial fibrosis but not proximal tubule cell apoptosis. Our study shows that the intrarenal renin-angiotensin system stimulates proximal tubule cell apoptosis and tubulointerstitial fibrosis, in part, by enhanced NADPH oxidase activity and reactive oxygen species generation independent of systemic hypertension.

• Authors: Fang Liu, Chih-Chang Wei, Shyh-Jong Wu, Isabelle Chenier, Shao-Ling Zhang, Janos G Filep, Julie R Ingelfinger, John S D Chan
• Journal: Kidney international (Kidney Int) Vol. 75 Issue 2 Pg. 156-66 (Jan 2009) ISSN: 1523-1755 [Electronic] United States
• PMID: 18923387 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Reactive Oxygen Species
• acetovanillone
• NADPH Oxidases

Topics

• Acetophenones (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Fibrosis (drug therapy)
• Hypertension
• Kidney Tubules (drug effects, pathology)
• Mice
• Mice, Transgenic
• NADPH Oxidases (antagonists & inhibitors)
• Reactive Oxygen Species (metabolism)
• Renin-Angiotensin System (drug effects)