Renal protective effects of aliskiren beyond its antihypertensive property in a mouse model of progressive fibrosis.

Abstract

BACKGROUND:

The direct renin inhibitor aliskiren is known to exhibit a strong antihypertensive effect. However, the organoprotective potential of aliskiren beyond its antihypertensive properties is less clear. This study investigates the antifibrotic nephroprotective effects of aliskiren in a nonhypertensive mouse model for progressive renal fibrosis.

METHODS:

COL4A3(-/-) mice received aliskiren via osmotic minipumps. Placebo-treated animals served as controls. Therapy was initiated in 6-week-old animals already showing renal damage (proteinuria ~1 g/l, starting renal fibrosis) and lasted for 4 weeks. Six animals were sacrificed after 9.5 weeks; serum urea and proteinuria were measured. Kidneys were further investigated using histological, immunohistological, and western blot techniques. Survival until end-stage renal failure was monitored in the remaining animals.

RESULTS:

COL4A3(-/-) mice did not develop hypertension. Aliskiren serum levels were in the therapeutic range (288 ± 44 ng/ml). Therapy significantly prolonged lifespan until death from renal failure by 18% compared with placebo-treated controls (78.6 ± 8.2 vs. 66.6 ± 4.9 days, P < 0.05). Similarly, therapy reduced the amount of proteinuria and serum urea. Compared with placebo-treated controls, the accumulation of extracellular matrix and renal scarring and the levels of transforming growth factor-β (TGFβ) and connective tissue growth factor (CTGF) were decreased in treated mice.

CONCLUSIONS:

Despite the late onset of therapy, our results indicate nephroprotective effects of the renin inhibitor aliskiren beyond its antihypertensive property in this animal model of progressive renal fibrosis. In addition to the recognized antihypertensive action of aliskiren, its antifibrotic, antiproteinuric effects demonstrated in the present study indicate that aliskiren may have potential as an important therapeutic option for chronic fibrotic diseases in humans.

• Authors: Oliver Gross, Rainer Girgert, Diana Rubel, Johanna Temme, Stephanie Theissen, Gerhard-Anton Müller
• Journal: American journal of hypertension (Am J Hypertens) Vol. 24 Issue 3 Pg. 355-61 (Mar 2011) ISSN: 1941-7225 [Electronic] United States
• PMID: 21127470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Angiotensin-Converting Enzyme Inhibitors
• Antihypertensive Agents
• Autoantigens
• Collagen Type IV
• Fumarates
• Transforming Growth Factor beta1
• type IV collagen alpha3 chain
• Connective Tissue Growth Factor
• aliskiren

Topics

• Amides (blood, pharmacology, therapeutic use)
• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Antihypertensive Agents (pharmacology)
• Autoantigens (physiology)
• Collagen Type IV (deficiency, physiology)
• Connective Tissue Growth Factor (analysis, biosynthesis)
• Disease Models, Animal
• Extracellular Matrix (metabolism)
• Fibrosis
• Fumarates (blood, pharmacology, therapeutic use)
• Kidney (drug effects, pathology)
• Mice
• Proteinuria (drug therapy)
• Transforming Growth Factor beta1 (analysis, biosynthesis)
• Uremia (prevention & control)