In several models of renal disease progression, angiotensin-converting enzyme (ACE) inhibitors reduced proteinuria and limited glomerulosclerosis, which suggested that reduction of renal angiotensin II (Ang II) activity is crucial for the preservation of glomerular structure and function. However, it cannot be ruled out that other hormonal systems, including inhibition of the bradykinin breakdown, also play a role. We compared the effects of chronic treatment with the ACE inhibitor lisinopril with those of a specific Ang II receptor antagonist, L-158,809, on proteinuria and renal injury in passive Heymann nephritis (PHN), a model of immune renal disease that closely resembles human membranous nephropathy, with long-lasting proteinuria followed by tubulointerstitial damage and glomerulosclerosis. Passive Heymann nephritis was induced with 0.5 mL/100 g of rabbit anti-Fx1A antibody in 24 male Sprague-Dawley rats. The animals were divided into three groups of eight rats each, and were given the following in the drinking water on a daily basis: lisinopril (40 mg/L), L-158,809 (50 mg/L), or no therapy. Treatment started at day 7 (proteinuria was already present) and lasted 12 months. Eight normal rats were used as controls. Untreated PHN rats developed hypertension, while rats with PHN given lisinopril or L-158,809 all had systolic blood pressure values even lower than those of normal rats. Urinary protein excretion progressively increased with time in untreated PHN rats, who developed tubulointerstitial damage and glomerulosclerosis. Both lisinopril and L-158,809 exhibited a potent antiproteinuric effect and preserved glomerular and tubular structural integrity at a similar extent. Renal gene expression of transforming growth factor-beta and extracellular matrix proteins was also effectively reduced by the two treatments. These results indicate that ACE inhibitors and Ang II receptor antagonists are equally effective in preventing renal injury in PHN and suggest that the renoprotective effects of ACE inhibitors in this model are solely due to inhibition of Ang II.

Mononuclear cell infiltration in glomeruli and renal interstitium is a prominent feature of some types of glomerulonephritis, including lupus nephritis. The mechanism(s) underlying monocyte influx into the kidney is not fully understood. Recently, monocyte chemoattractant protein-1 (MCP-1) has been identified as a chemotactic factor involved in the recruitment of monocytes/macrophages in the glomeruli of rats with mesangioproliferative as well as anti-glomerular basement membrane glomerulonephritis. In the study presented here, renal MCP-1 mRNA expression in New Zealand Black x New Zealand White (NZB/W) F1 mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans, was investigated. Northern blot analysis revealed a single 0.7 kb MCP-1 transcript of very low intensity in kidneys from 2-month-old NZB/W mice that had not yet developed proteinuria nor renal damage. Message levels, which increased markedly with the progression of nephritis and in association with mononuclear cell infiltration, were 10- and 15- fold higher in 8-10-month-old mice than in 2-month-old mice. By in situ hybridization, increased expression of MCP-1 mRNA was demonstrated in glomeruli and, even more striking, in tubular epithelial cells. Western blot analysis demonstrated increased expression of MCP-1 protein in kidneys of 10-month-old NZB/W mice, consistent with MCP-1 mRNA data. When NZB/W mice were treated with cyclophosphamide up to 12 months of age, expression of MCP-1 in the renal tissue remained low, the influx of inflammatory cells did not appear, and glomerular and tubular structures remained well preserved. These data suggest that elevated MCP-1 might act as a signal for inflammatory cells to infiltrate the kidney in lupus nephritis.