Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney

Background. Macrophage (M phi) infiltration may contribute to chronic renal injury. We therefore sought to examine the expression of genes associated with M phi recruitment in the rat remnant kidney model. Methods. Male Munich Wistar rats underwent 5/6 nephrectomy or sham operation (SHM, N = 18) and received no treatment (VEH, N = 18), enalapril 100 mg/L (ENA, N = 18), or candesartan 70 mg/L (CSN, N = 24) in drinking water. Competitive, quantitative reverse transcription-polymerase chain reaction was used to determine renal cortex mRNA levels for cell adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), the M phi chemoattractant monocyte chemoattractant protein-1 (MCP-1), M phi products interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), and the profibrotic cytokine transforming growth factor-beta 1 (TGF-beta 1), at intervals post-nephrectomy. Results. Glomerular and interstitial M phi infiltration in VEH rats was associated with an early (4 week) and sustained rise in MCP-1 and TGF-beta 1 mRNA levels. Progressive increases in ICAM-1, VCAM-1, IL-1 beta. and TNF-alpha expression followed at 8 and 12 weeks. Immunostaining in VEH rats localized TGF-beta 1 to glomeruli, tubules. and interstitium; MCP-1 to tubules and interstitial cells: ICAM-1 to glomeruli: and IL-1 beta and TNF-alpha to tubules and interstitial cells. At 12 weeks, both treatments normalized systolic blood pressure (ENA, 105 +/- 6; CSN. 97 +/- 3 mm Hg) and the urinary protein excretion rate (ENA, 8.4 +/- 0.9; CSN, 5.7 +/- 0.8 mg/day), prevented renal injury (focal and segmental glomerulosclerosis: ENA, 3.3 +/- 0.9; CSN, 1.3 +/- 0.4%), and suppressed M phi infiltration and cytokine expression (with the exception of TNF-alpha) to near SHM levels. Conclusions. These findings support the hypothesis that the coordinated up-regulation of several molecules regulating M phi recruitment and activation is a fundamental response to renal mass ablation and is dependent on an intact renin-angiotensin system. We speculate that these responses may play a role in the pathogenesis of the ensuing glomerulosclerosis and tubulointerstitial fibrosis.