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Published on: November 7, 2017
The renal lesions that develop in neonatal mice during angiotensin inhibition mimic obstructive nephropathy
Y Miyazaki1, S Tsuchida, A Fogo
1Department of Pediatrics, Vanderbilt University Medical Center Nashville, Tennessee, USA.
Background:
Inhibition of angiotensin action, pharmacologically or genetically, during the neonatal period leads to renal anomalies involving hypoplastic papilla and dilated calyx. Recently, we documented that angiotensinogen (Agt -/-) or angiotensin type 1 receptor nullizygotes (Agtr1 -/-) do not develop renal pelvis nor ureteral peristaltic movement, both of which are essential for isolating the kidney from the high downstream ureteral pressure. We therefore examined whether these renal anomalies could be characterized as "obstructive" nephropathy.
Methods:
Agtr1 -/- neonatal mice were compared with wild-type neonates, the latter subjected to surgical complete unilateral ureteral ligation (UUO), by analyzing morphometrical, immunohistochemical, and molecular indices. Agtr1 -/- mice were also subjected to a complete UUO and were compared with wild-type UUO mice by quantitative analysis. To assess the function of the urinary tract, baseline pelvic and ureteral pressures were measured.
Results:
The structural anomalies were qualitatively indistinguishable between the Agtr1 -/- without surgical obstruction versus the wild type with complete UUO. Thus, in both kidneys, the calyx was enlarged, whereas the papilla was atrophic; tubulointerstitial cells underwent proliferation and also apoptosis. Both were also characterized by interstitial macrophage infiltration and fibrosis, and within the local lesion, transforming growth factor-beta 1, platelet-derived growth factor-A and insulin-like growth factor-1 were up-regulated, whereas epidermal growth factor was down-regulated. Moreover, quantitative differences that exist between mutant kidneys without surgical obstruction and wild-type kidneys with surgical UUO were abolished when both underwent the same complete surgical UUO. The hydraulic baseline pressure was always lower in the pelvis than that in the ureter in the wild type, whereas this pressure gradient was reversed in the mutant.
Conclusion:
The abnormal kidney structure that develops in neonates during angiotensin inhibition is attributed largely to "functional obstruction" of the urinary tract caused by the defective development of peristaltic machinery.
Insights
Neonatal angiotensin inhibition causes kidney anomalies by creating a functional obstruction due to impaired ureteral peristalsis. This leads to conditions like hypoplastic papilla and dilated calyx, mimicking obstructive nephropathy.
Area of Science:
- Nephrology
- Developmental Biology
- Renal Physiology
Background:
- Neonatal inhibition of angiotensin action leads to renal anomalies, including hypoplastic papilla and dilated calyx.
- Angiotensinogen (Agt -/-) or angiotensin type 1 receptor nullizygote (Agtr1 -/-) mice lack renal pelvis and ureteral peristalsis, crucial for managing downstream ureteral pressure.
- These findings suggest a potential link between angiotensin signaling defects and obstructive nephropathy.
Purpose of the Study:
- To investigate whether renal anomalies resulting from neonatal angiotensin inhibition can be classified as obstructive nephropathy.
- To compare the renal structural and functional changes in Agtr1 -/- mice with those in wild-type mice undergoing unilateral ureteral obstruction (UUO).
Main Methods:
- Morphometrical, immunohistochemical, and molecular analyses were performed on Agtr1 -/- neonates and wild-type neonates with surgical UUO.
- Quantitative analysis compared Agtr1 -/- mice subjected to UUO with wild-type UUO mice.
- Baseline pelvic and ureteral pressures were measured to assess urinary tract function.
Main Results:
- Structural anomalies in Agtr1 -/- mice without obstruction were indistinguishable from wild-type mice with UUO, showing enlarged calyces, atrophic papilla, tubulointerstitial cell changes, fibrosis, and altered growth factor expression.
- Quantitative differences between mutant kidneys without obstruction and wild-type kidneys with UUO were abolished when both underwent UUO.
- A reversed pressure gradient (pelvis pressure higher than ureter pressure) was observed in Agtr1 -/- mutants compared to wild-type mice.
Conclusions:
- The abnormal kidney structure in neonates with angiotensin inhibition is largely due to functional obstruction of the urinary tract.
- This functional obstruction arises from defective development of the ureteral peristaltic machinery.
- Angiotensin signaling plays a critical role in normal urinary tract development and function, preventing obstructive nephropathy.
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