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ACE inhibition prevents renal failure and death in uninephrectomized MWF/Ztm rats
A Remuzzi1, A Benigni, B Malanchini
1Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Abstract:
Many studies have consistently documented that angiotensin converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in progressive renal disease, but very few data are available on whether they also prevent renal failure and death. The mechanisms of the beneficial effect of ACE inhibition are only partially understood. Recent data suggest that angiotensin II modulates renal synthesis of endothelin-1, a vasoactive peptide implicated in the process of renal injury. Here we investigated in a long-term study whether ACE inhibition ameliorated renal function in uninephrectomized (UNx) male MWF/Ztm rats. Three groups of rats at nine weeks of age underwent UNx or sham-operation. Nephrectomized animals were left untreated or treated with the ACE inhibitor lisinopril in drinking water. In untreated UNx animals systolic blood pressure, serum creatinine, urinary protein and renal synthesis of endothelin-1, evaluated by its urinary excretion, were significantly increased, as compared with control animals with two kidneys. End-stage renal failure developed in all untreated UNx rats that died within 9 to 14 months from UNx. ACE inhibitor significantly reduced systolic blood pressure, completely prevented proteinuria and renal function deterioration, and reduced endothelin-1 excretion. All UNx rats treated with lisinopril were alive 14 months after UNx. These results show that ACE inhibition prevents end-stage renal failure induced by UNx in male MWF/Ztm, and that the beneficial effects of angiotensin II inhibition in this model are related to modulation of renal synthesis of endothelin-1.
Insights
Angiotensin converting enzyme (ACE) inhibitors prevent kidney failure and death in rats with reduced kidney mass. This study shows ACE inhibition reduces blood pressure and endothelin-1, preserving renal function.
Area of Science:
- Nephrology
- Cardiovascular Research
- Pharmacology
Background:
- Angiotensin converting enzyme (ACE) inhibitors are known to prevent proteinuria and glomerulosclerosis in progressive renal disease.
- However, their effect on preventing renal failure and death is less understood.
- Angiotensin II may modulate renal endothelin-1 synthesis, a peptide implicated in renal injury.
Purpose of the Study:
- To investigate the long-term effects of ACE inhibition on renal function in uninephrectomized (UNx) male MWF/Ztm rats.
- To determine if ACE inhibition prevents end-stage renal failure and death in this model.
- To explore the role of endothelin-1 in the protective mechanisms of ACE inhibition.
Main Methods:
- Male MWF/Ztm rats underwent uninephrectomy (UNx) or sham-operation at nine weeks of age.
- UNx rats were either left untreated or treated with the ACE inhibitor lisinopril in drinking water.
- Systolic blood pressure, serum creatinine, urinary protein, and urinary endothelin-1 excretion were measured.
Main Results:
- Untreated UNx rats showed increased systolic blood pressure, serum creatinine, urinary protein, and endothelin-1 excretion compared to controls.
- All untreated UNx rats developed end-stage renal failure and died within 9–14 months.
- Lisinopril treatment significantly reduced blood pressure, prevented proteinuria and renal function decline, and decreased endothelin-1 excretion.
- All lisinopril-treated UNx rats survived for 14 months.
Conclusions:
- ACE inhibition effectively prevents end-stage renal failure and death in male MWF/Ztm rats following uninephrectomy.
- The beneficial effects of ACE inhibition in this model are associated with the modulation of renal endothelin-1 synthesis.
- ACE inhibitors represent a crucial therapeutic strategy for preserving renal function in conditions of reduced kidney mass.