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Updated: Aug 1, 2026
Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney
M W Taal1, K Zandi-Nejad, B Weening
1Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115-6110, USA. mtaal@rics.bwh.harvard.edu
Background:
Macrophage (Mphi) infiltration may contribute to chronic renal injury. We therefore sought to examine the expression of genes associated with Mphi 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 Mphi chemoattractant monocyte chemoattractant protein-1 (MCP-1), Mphi products interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), and the profibrotic cytokine transforming growth factor-beta1 (TGF-beta1), at intervals post-nephrectomy.
Results:
Glomerular and interstitial Mphi infiltration in VEH rats was associated with an early (4 week) and sustained rise in MCP-1 and TGF-beta1 mRNA levels. Progressive increases in ICAM-1, VCAM-1, IL-1beta, and TNF-alpha expression followed at 8 and 12 weeks. Immunostaining in VEH rats localized TGF-beta1 to glomeruli, tubules, and interstitium; MCP-1 to tubules and interstitial cells; ICAM-1 to glomeruli; and IL-1beta 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 Mphi 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 Mphi 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.
Insights
Macrophage infiltration drives chronic kidney injury after nephrectomy. ACE inhibitors and ARBs reduced this infiltration and protected against renal damage by targeting the renin-angiotensin system.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Macrophage infiltration is implicated in chronic kidney injury.
- Investigating gene expression related to macrophage recruitment in a rat remnant kidney model is crucial.
Purpose of the Study:
- To examine the expression of genes involved in macrophage recruitment in the rat remnant kidney model.
- To assess the effects of enalapril and candesartan on these gene expressions and renal injury.
Main Methods:
- Utilized a rat remnant kidney model (5/6 nephrectomy).
- Employed quantitative reverse transcription-polymerase chain reaction to measure mRNA levels of key genes (VCAM-1, ICAM-1, MCP-1, IL-1beta, TNF-alpha, TGF-beta1).
- Administered enalapril or candesartan and evaluated systolic blood pressure, urinary protein excretion, and renal histology.
Main Results:
- Vehicle-treated rats showed increased macrophage infiltration, MCP-1, and TGF-beta1, followed by ICAM-1, VCAM-1, IL-1beta, and TNF-alpha.
- Both enalapril and candesartan normalized blood pressure and proteinuria.
- Treatments significantly reduced renal injury, macrophage infiltration, and most cytokine expressions compared to vehicle control.
Conclusions:
- Coordinated upregulation of molecules regulating macrophage recruitment is a key response to renal mass ablation.
- This response is dependent on the renin-angiotensin system.
- These molecular changes may contribute to glomerulosclerosis and tubulointerstitial fibrosis in chronic kidney disease.
