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Expression of subunits of the metalloendopeptidase meprin in renal cortex in experimental hydronephrosis
S D Ricardo1, J S Bond, G D Johnson
1Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania 17033, USA.
Abstract:
Meprin A is a metalloendopeptidase in the proximal tubular epithelium of rodents that is capable of hydrolyzing a great variety of peptides and proteins. The aim of the present investigation was to investigate effects of ureteral ligation on the expression of meprin subunits. Ureteral ligation resulted in marked decreases in the expression of both alpha- and beta-meprin subunits within 12 h of ureteral obstruction. Even greater downregulation of expression of meprin alpha- and beta-mRNA was noted at 24, 48, and 96 h after ureteral ligation. The greatest decrease in meprin mRNA expression in obstructed kidneys over contralateral unobstructed control kidneys (CUK) occurred at 24 h postunilateral ureteral obstruction (post-UUO) for the meprin alpha-subunit (20-fold decrease compared with controls) and at 48 h for the meprin beta-subunit (90-fold decrease). On immunolabeling, the intensity for the two meprin subunits at the corticomedullary junction was dramatically decreased at 24 to 96 h after ureteral ligation in contrast to the CUK specimens. Results of in situ hybridization indicated that the CUK specimens expressed meprin beta-mRNA at the corticomedullary junction, whereas the obstructed kidneys exhibited a decrease in mRNA signal for meprin beta-subunit. There was a steady increase in the interstitial macrophage number in UUO rat kidneys over the 96 h of evaluation post-UUO. ED-1-positive macrophages were observed almost exclusively in the peritubular cortical interstitial space in a ringlike pattern with a preponderance of macrophage clusters around glomeruli. Unexpectedly, after reversal of UUO, the interstitial macrophage number remained higher than controls, despite the demonstrable decompression of the renal pelvis and caliceal system. In summary, this investigation demonstrates downregulation of meprin alpha and beta within hours of UUO and indicates a novel tubular response to ureteral obstruction.
Insights
Unilateral ureteral obstruction (UUO) significantly downregulates meprin alpha and beta expression in rodent kidneys within hours. This study reveals a novel tubular response to ureteral obstruction, impacting protein expression and macrophage infiltration.
Area of Science:
- Nephrology
- Molecular Biology
- Renal Physiology
Background:
- Meprin A, a metalloendopeptidase in rodent proximal tubular epithelium, processes various peptides and proteins.
- Understanding the regulation of meprin subunits is crucial for comprehending renal physiology and pathology.
Purpose of the Study:
- To investigate the effects of ureteral ligation on the expression of meprin alpha and beta subunits in rodent kidneys.
- To elucidate the temporal changes in meprin subunit and mRNA expression following ureteral obstruction.
Main Methods:
- Unilateral ureteral ligation (UUO) was performed on rodents.
- Meprin subunit and mRNA expression were analyzed using immunolabeling and in situ hybridization.
- Interstitial macrophage populations were quantified using ED-1 staining.
Main Results:
- Ureteral ligation caused a rapid and marked decrease in both meprin alpha and beta subunit expression within 12 hours.
- Meprin alpha and beta mRNA levels were significantly downregulated, with the greatest decrease observed at 24 and 48 hours post-UUO, respectively.
- A progressive increase in interstitial macrophages was observed in obstructed kidneys, persisting even after obstruction reversal.
Conclusions:
- Ureteral obstruction leads to rapid downregulation of meprin alpha and beta expression in the kidney.
- This downregulation represents a novel tubular response to ureteral obstruction.
- Persistent interstitial macrophage infiltration suggests a complex inflammatory response following ureteral obstruction and decompression.