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Published ahead of print on February 23, 2005
J Am Soc Nephrol 16: 966-976, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2004060492
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Basic Immunology and Pathology

Regression of Glomerulosclerosis with High-Dose Angiotensin Inhibition Is Linked to Decreased Plasminogen Activator Inhibitor-1

Li-Jun Ma, Shinya Nakamura, Jean Claude Aldigier, Michele Rossini, Haichun Yang, Xiubin Liang, Ikuko Nakamura, Carmelita Marcantoni and Agnes B. Fogo

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee

Address correspondence to: Dr. Agnes B. Fogo, MCN C3310, Department of Pathology, Vanderbilt University Medical Center, 21st and Garland Avenue, Nashville, TN 37232-2561. Phone: 615-322-3114; Fax: 615-343-7023; E-mail: agnes.fogo{at}vanderbilt.edu

Received for publication June 22, 2004. Accepted for publication January 5, 2005.

The potential and possible mechanisms for regression of existing glomerulosclerosis by angiotensin II type 1 receptor antagonist (AT1RA) and/or angiotensin I converting enzyme inhibitor (ACEI) were investigated. Adult male Sprague Dawley rats underwent 5/6 nephrectomy (Nx). Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into groups with equal biopsy sclerosis and treated for the next 4 wk until they were killed at 12 wk as follows: Control with no further treatment (CONT), high-dose AT1RA, high-dose ACEI, and varying AT1RA+ACEI combinations. Hypertension and proteinuria induced by 5/6 Nx were significantly decreased by all treatments, except high-dose ACEI, which showed persistent proteinuria. High-dose AT1RA and ACEI markedly decreased progression of sclerosis, with –2.3% average decrease in sclerosis from biopsy to autopsy in AT1RA versus 194% increase in CONT (P < 0.0001). Glomerulosclerosis regressed, with less severe lesions at the time when the rats were killed than at biopsy in 62% of AT1RA-treated and 57% of ACEI-treated rats. In contrast, only 17 to 33% of rats in combination groups had regression. Alternatively, these data might be viewed as reflecting halting of progression, as some groups had higher BP and proteinuria. However, this potential confounding effect does not negate the effects to achieve regression of sclerosis in these rats. Regression was not explained by changes in mRNA of TGF-{beta}1 and matrix metalloproteinase-2 and -9 but was linked to decreased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. It is concluded that angiotensin inhibition mediates regression in part by effects on matrix modulation.




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