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 operatio n (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. Com petitive, quantitative reverse transcription-polymerase chain reaction was used to determine renal cortex mRNA levels for cell adhesion molecules vasc ular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule- 1 (ICAM-1), the M phi chemoattractant monocyte chemoattractant protein-1 (M CP-1), M phi products interleukin-1 beta (IL-1 beta) and tumor necrosis fac tor-alpha (TNF-alpha), and the profibrotic cytokine transforming growth fac tor-beta 1 (TGF-beta 1), at intervals post-nephrectomy. Results. Glomerular and interstitial M phi infiltration in VEH rats was ass ociated with an early (4 week) and sustained rise in MCP-1 and TGF-beta 1 m RNA levels. Progressive increases in ICAM-1, VCAM-1, IL-1 beta. and TNF-alp ha expression followed at 8 and 12 weeks. Immunostaining in VEH rats locali zed TGF-beta 1 to glomeruli, tubules. and interstitium; MCP-1 to tubules an d interstitial cells: ICAM-1 to glomeruli: and IL-1 beta and TNF-alpha to t ubules and interstitial cells. At 12 weeks, both treatments normalized syst olic blood pressure (ENA, 105 +/- 6; CSN. 97 +/- 3 mm Hg) and the urinary p rotein excretion rate (ENA, 8.4 +/- 0.9; CSN, 5.7 +/- 0.8 mg/day), prevente d renal injury (focal and segmental glomerulosclerosis: ENA, 3.3 +/- 0.9; C SN, 1.3 +/- 0.4%), and suppressed M phi infiltration and cytokine expressio n (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 in tact renin-angiotensin system. We speculate that these responses may play a role in the pathogenesis of the ensuing glomerulosclerosis and tubulointer stitial fibrosis.