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The role of meprin A in the pathogenesis of acute renal failure
H Trachtman1, E Valderrama, J M Dietrich
1Department of Pediatrics, Schneider Children's Hospital, New Hyde Park, NY 11040.
Abstract:
Meprin A is a zinc-dependent metallo-endopeptidase that is present in the brush border membrane of renal proximal tubular epithelial cells. Although this enzyme has been detected in the kidney of mammalian species and its biochemical structure and action have been characterized, the role of this endopeptidase in normal renal physiology and in disease states is unknown. Therefore, we assessed the susceptibility of inbred strains of mice with normal and low meprin A activity to ischemic and nephrotoxic acute renal failure. We report that two normal meprin A strains of mice, C57BL/6 and DBA/2, developed more severe renal functional and structural injury following either bilateral renal artery clamping or the injection of hypertonic glycerol, compared to two low meprin A strains, C3H/He and CBA. These findings suggest that meprin A plays a role in the pathophysiology of acute renal failure following a variety of insults to the kidney. We propose that redistribution of this metalloendopeptidase to the basolateral membrane domain during acute renal failure results in degradation of the extracellular matrix and damage to adjacent peritubular structures.
Insights
Meprin A, an enzyme in kidney cells, worsens acute kidney injury. Mice with low meprin A activity showed less damage from kidney insults, suggesting a protective role.
Area of Science:
- Nephrology
- Biochemistry
- Enzymology
Background:
- Meprin A is a zinc-dependent metallo-endopeptidase found in renal proximal tubular epithelial cells.
- Its precise role in kidney physiology and disease remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of meprin A in acute renal failure (ARF).
- To assess the susceptibility of mice with varying meprin A activity to kidney injury.
Main Methods:
- Utilized inbred mouse strains with differing meprin A activity levels (C57BL/6, DBA/2 - normal; C3H/He, CBA - low).
- Induced ARF using bilateral renal artery clamping (ischemic injury) and hypertonic glycerol injection (nephrotoxic injury).
- Evaluated renal functional and structural damage.
Main Results:
- Normal meprin A activity strains (C57BL/6, DBA/2) exhibited more severe renal injury compared to low meprin A activity strains (C3H/He, CBA).
- This difference was observed in both ischemic and nephrotoxic models of ARF.
Conclusions:
- Meprin A appears to contribute to the pathophysiology of acute renal failure.
- Proposed mechanism involves meprin A redistribution to the basolateral membrane, leading to extracellular matrix degradation and peritubular damage.