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Mild renal ischemia activates primed neutrophils to cause acute renal failure
S L Linas1, D Whittenburg, P E Parsons
1University of Colorado Health Sciences Center, Webb Waring Lung Institute, Denver General Hospital.
Abstract:
The role of neutrophils (PMN) in acute renal failure (ARF) is controversial. Although the development of acute renal failure (ARF) frequently occurs in situations where there is partial activation of PMN (primed PMN) and mild renal ischemia, the interaction between primed PMN and ischemic organs has not been studied in any biological system. To define the interaction between primed PMN and mild renal ischemia, kidneys were made ischemic for 10 minutes in situ and reperfused by the isolated kidney technique with untreated PMN or PMN primed with low concentrations of lipopolysaccharide (LPS) or phorbol myristate acetate (PMA). We found that primed PMN had no effect on control (non-ischemic) kidneys and that untreated PMN did not cause injury to kidneys previously subjected to mild ischemia. However, addition of primed PMN to mildly ischemic kidneys caused severe injury. To determine the nature of renal injury, ischemic kidneys were reperfused with primed PMN and catalase (CAT) or the elastase inhibitor, Eglin C. In ischemic kidneys reperfused with LPS-primed PMN, Eglin C (but not CAT) was partially protective while in ischemic kidneys reperfused with PMA-primed PMN, CAT (but not Eglin C) was partially protective. Reperfusion with both CAT and Eglin C completely prevented the damaging effects of either LPS- or PMA-primed PMN. In conclusion, addition of primed but not untreated PMN causes ARF in mildly ischemic kidneys by PMN oxidant- and/or protease-mediated mechanisms. This synergism could account for the high frequency of ARF in conditions associated with prerenal azotemia and primed PMN.
Insights
Primed neutrophils, but not untreated ones, cause acute renal failure (ARF) in mildly ischemic kidneys. This injury involves neutrophil oxidants and proteases, explaining ARF
Area of Science:
- Nephrology
- Immunology
- Pathophysiology
Background:
- The role of neutrophils (PMN) in acute renal failure (ARF) remains controversial.
- ARF often occurs with primed PMN and mild renal ischemia, but their interaction is poorly understood.
Purpose of the Study:
- To investigate the interaction between primed neutrophils and mildly ischemic kidneys.
- To elucidate the mechanisms of renal injury induced by primed neutrophils in ischemia.
Main Methods:
- Isolated rat kidneys underwent 10 minutes of ischemia followed by reperfusion.
- Kidneys were reperfused with untreated PMN, LPS-primed PMN, or PMA-primed PMN.
- Protective effects of catalase (CAT) and elastase inhibitor (Eglin C) were assessed.
Main Results:
- Primed PMN caused severe injury to mildly ischemic kidneys; untreated PMN did not.
- LPS-primed PMN injury was partially reduced by Eglin C; PMA-primed PMN injury was partially reduced by CAT.
- Combined CAT and Eglin C completely prevented injury from both LPS- and PMA-primed PMN.
Conclusions:
- Primed neutrophils, not untreated neutrophils, induce ARF in mildly ischemic kidneys.
- Neutrophil-mediated oxidant and protease activity are key mechanisms in this synergistic injury.
- This interaction may explain ARF frequency in conditions with prerenal azotemia and primed PMN.