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The Molecular Basis of Increased Glomerulosclerosis after Blockade of the Renin Angiotensin System in Growth Hormone Transgenic Mice

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Abstract

Background

Angiotensin converting enzyme inhibitor (ACEi) therapy delays the onset of renal failure in diabetic nephropathy and inhibits or delays the onset of proteinuria in several animal models.

Materials and Methods

We examined this question using a transgenic model of chronic glomerulosclerosis caused by an excess production of growth hormone (GH) in which there is progressive glomerular scarring leading to uremia. In addition, since GH mice do not have systemic hypertension or an elevated glomerular filtration rate, we could address the question of whether ACEi or angiotensin II receptor antagonists (AII RA) had an effect on the development of glomerulosclerosis under these conditions. Since excess matrix accumulates in glomerulosclerosis because of alterations in the balance between its synthesis and degradation, we examined the effect of ACEi and AII RA on these parameters.

Results

Systemic blood pressure was unaffected by ACEi treatment, but the glomerular filtration rate decreased 85%. ACEi-treated mice had increased mesangial deposition of type I collagen and decreased 105 kD complex collagenase activity. In addition, ACEi-treated GH mice had increased glomerular α1 type I collagen, α1 type IV collagen, and α-smooth muscle cell actin mRNAs. No changes were noted in β actin, or 72 kD metalloproteinase mRNAs. The result of these changes was a net increase in sclerosis. Surprisingly, GH mice treated with ACEi or AngII RA developed marked renal arteriolar lesions.

Conclusions In some forms of glomerulosclerosis, the lesions develop independently of angiotensin II. Pharmacological inhibition of angiotensin II, in this circumstance, may aggravate the lesions through disregulation of the levels and the balance between glomerular matrix synthesis and degradation

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Acknowledgments

The authors wish to thank Dr. K. Catt for critical evaluation of this work. Dr. K. Flanders for the TGF-β antibodies, and Drs. P. Corvol and J. Gasc for the renin antibody. This study was supported by the Juvenile Diabetes Foundation International (E.P.P., Career Development Award), by the American Diabetic Association (L.J.S., Mentor-based Post-doctoral Fellowship Award), and by the National Institutes of Health (DIR, NIDDK, and Research Grants DK 42131 to A.F., DK 44757 to A.F. and I.I., and DK 37868 to I.I.).

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Authors and Affiliations

  1. Renal Cell Biology Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA

    Emmanuel P. Peten, Liliane J. Striker, Aneeta Patel & Gary E. Striker

  2. Department of Pediatrics and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Agnes Fogo & Iekuni Ichikawa

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  1. Emmanuel P. Peten
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  2. Liliane J. Striker
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  6. Gary E. Striker
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Peten, E.P., Striker, L.J., Fogo, A. et al. The Molecular Basis of Increased Glomerulosclerosis after Blockade of the Renin Angiotensin System in Growth Hormone Transgenic Mice. Mol Med 1, 104–115 (1994). https://doi.org/10.1007/BF03403536

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