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Mild ischemic injury leads to long-term alterations in the kidney: amelioration by spironolactone administration.

Barrera-Chimal J, Pérez-Villalva R, Ortega JA, Sánchez A, Rodríguez-Romo R, Durand M, Jaisser F, Bobadilla NA - Int. J. Biol. Sci. (2015)

Bottom Line: These effects were associated with activation of the transforming growth factor β (TGFβ) signaling pathway and up-regulation of endothelin receptor A (ETA) and alpha smooth muscle actin (αSMA).Spironolactone treatment immediately or 1.5-h after the ischemic insult prevented the onset of these disorders.Our results show that moderate ischemic insult leads to long-term structural and molecular changes that may compromise renal function in later stages.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México ; 2. Nephrology Department of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán ; 4. INSERM U1138, Centre de Recherche de Cordeliers, Team 1, Paris, France.

ABSTRACT
Administration of the mineralocorticoid receptor antagonist spironolactone prevents the development of chronic kidney disease (CKD) after a severe ischemic injury. However, whether brief periods of ischemia lead to CKD and whether spironolactone administration after ischemia may be a useful therapeutic strategy to prevent the gradual deterioration of structure and function remains unexplored. Nineteen male Wistar rats were divided into four groups: rats that underwent renal bilateral ischemia for 10, 20, or 45 min were compared with sham operated rats. Additionally, thirteen male Wistar rats that underwent renal bilateral ischemia for 20 min were divided into an untreated ischemic group (I) and two groups receiving spironolactone, 20 mg/kg by gavage, at either 0 (Sp0) or 1.5-h after ischemia (Sp1.5). The rats were followed up and studied after 9 months. Mild (20 min) and severe (45 min) ischemia induced a progressive increase in proteinuria at varying magnitudes, whereas minor ischemia (10 min) did not modify proteinuria. CKD induced by moderate ischemia was characterized by renal hypertrophy and tubulointerstitial fibrosis. These effects were associated with activation of the transforming growth factor β (TGFβ) signaling pathway and up-regulation of endothelin receptor A (ETA) and alpha smooth muscle actin (αSMA). Spironolactone treatment immediately or 1.5-h after the ischemic insult prevented the onset of these disorders. Our results show that moderate ischemic insult leads to long-term structural and molecular changes that may compromise renal function in later stages. Additionally, we demonstrate that spironolactone administration after mild ischemia prevents this detrimental effect.

No MeSH data available.


Related in: MedlinePlus

Mild acute kidney injury leads to the development of proteinuria, and the effect was ameliorated by spironolactone administration. Four groups were included: sham (S, n=4), rats that underwent bilateral renal ischemia for 20 min (UTxI, n=5) and rats that received spironolactone (20 mg/kg) at 0 or 1.5 hours after ischemia (Sp0, and Sp1.5, respectively, n=4). A) Urinary protein excretion was determined every 30 days during the follow-up: sham (black circles), A-C (black squares), Sp0 (gray squares) and Sp1.5 (gray triangles). At the end of the 9-month period, B) creatinine clearance, C) renal blood flow and D) mean arterial pressure were determined in the sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). *p<0.05 vs. sham operated rats and ⌘P<0.05 vs. the UTxI group.
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Figure 2: Mild acute kidney injury leads to the development of proteinuria, and the effect was ameliorated by spironolactone administration. Four groups were included: sham (S, n=4), rats that underwent bilateral renal ischemia for 20 min (UTxI, n=5) and rats that received spironolactone (20 mg/kg) at 0 or 1.5 hours after ischemia (Sp0, and Sp1.5, respectively, n=4). A) Urinary protein excretion was determined every 30 days during the follow-up: sham (black circles), A-C (black squares), Sp0 (gray squares) and Sp1.5 (gray triangles). At the end of the 9-month period, B) creatinine clearance, C) renal blood flow and D) mean arterial pressure were determined in the sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). *p<0.05 vs. sham operated rats and ⌘P<0.05 vs. the UTxI group.

Mentions: We next evaluated the effectiveness of post-ischemic treatment with spironolactone to prevent long-term functional, structural and molecular damage. The progressive increase of proteinuria induced by 20-min of ischemia was significantly lessened after nine months in the groups treated with spironolactone immediately (Sp0) or 1.5-h (Sp1.5) after ischemia (63.7 ± 18.5  and 66.1 ± 19.2 mg/day, respectively) (Figure 2A). Despite the presence of proteinuria in the untreated ischemic group, the rats did not exhibit renal dysfunction at the end of the experiment; similar values of renal blood flow and creatinine clearance were observed among the groups (Figures 2B and 2C). None of the rats presented with an increase in mean arterial pressure, indicating that phenotypic changes are directly related to the duration of ischemia and not secondary to systemic hypertension (Figure 2D).


Mild ischemic injury leads to long-term alterations in the kidney: amelioration by spironolactone administration.

Barrera-Chimal J, Pérez-Villalva R, Ortega JA, Sánchez A, Rodríguez-Romo R, Durand M, Jaisser F, Bobadilla NA - Int. J. Biol. Sci. (2015)

Mild acute kidney injury leads to the development of proteinuria, and the effect was ameliorated by spironolactone administration. Four groups were included: sham (S, n=4), rats that underwent bilateral renal ischemia for 20 min (UTxI, n=5) and rats that received spironolactone (20 mg/kg) at 0 or 1.5 hours after ischemia (Sp0, and Sp1.5, respectively, n=4). A) Urinary protein excretion was determined every 30 days during the follow-up: sham (black circles), A-C (black squares), Sp0 (gray squares) and Sp1.5 (gray triangles). At the end of the 9-month period, B) creatinine clearance, C) renal blood flow and D) mean arterial pressure were determined in the sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). *p<0.05 vs. sham operated rats and ⌘P<0.05 vs. the UTxI group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495407&req=5

Figure 2: Mild acute kidney injury leads to the development of proteinuria, and the effect was ameliorated by spironolactone administration. Four groups were included: sham (S, n=4), rats that underwent bilateral renal ischemia for 20 min (UTxI, n=5) and rats that received spironolactone (20 mg/kg) at 0 or 1.5 hours after ischemia (Sp0, and Sp1.5, respectively, n=4). A) Urinary protein excretion was determined every 30 days during the follow-up: sham (black circles), A-C (black squares), Sp0 (gray squares) and Sp1.5 (gray triangles). At the end of the 9-month period, B) creatinine clearance, C) renal blood flow and D) mean arterial pressure were determined in the sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). *p<0.05 vs. sham operated rats and ⌘P<0.05 vs. the UTxI group.
Mentions: We next evaluated the effectiveness of post-ischemic treatment with spironolactone to prevent long-term functional, structural and molecular damage. The progressive increase of proteinuria induced by 20-min of ischemia was significantly lessened after nine months in the groups treated with spironolactone immediately (Sp0) or 1.5-h (Sp1.5) after ischemia (63.7 ± 18.5  and 66.1 ± 19.2 mg/day, respectively) (Figure 2A). Despite the presence of proteinuria in the untreated ischemic group, the rats did not exhibit renal dysfunction at the end of the experiment; similar values of renal blood flow and creatinine clearance were observed among the groups (Figures 2B and 2C). None of the rats presented with an increase in mean arterial pressure, indicating that phenotypic changes are directly related to the duration of ischemia and not secondary to systemic hypertension (Figure 2D).

Bottom Line: These effects were associated with activation of the transforming growth factor β (TGFβ) signaling pathway and up-regulation of endothelin receptor A (ETA) and alpha smooth muscle actin (αSMA).Spironolactone treatment immediately or 1.5-h after the ischemic insult prevented the onset of these disorders.Our results show that moderate ischemic insult leads to long-term structural and molecular changes that may compromise renal function in later stages.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México ; 2. Nephrology Department of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán ; 4. INSERM U1138, Centre de Recherche de Cordeliers, Team 1, Paris, France.

ABSTRACT
Administration of the mineralocorticoid receptor antagonist spironolactone prevents the development of chronic kidney disease (CKD) after a severe ischemic injury. However, whether brief periods of ischemia lead to CKD and whether spironolactone administration after ischemia may be a useful therapeutic strategy to prevent the gradual deterioration of structure and function remains unexplored. Nineteen male Wistar rats were divided into four groups: rats that underwent renal bilateral ischemia for 10, 20, or 45 min were compared with sham operated rats. Additionally, thirteen male Wistar rats that underwent renal bilateral ischemia for 20 min were divided into an untreated ischemic group (I) and two groups receiving spironolactone, 20 mg/kg by gavage, at either 0 (Sp0) or 1.5-h after ischemia (Sp1.5). The rats were followed up and studied after 9 months. Mild (20 min) and severe (45 min) ischemia induced a progressive increase in proteinuria at varying magnitudes, whereas minor ischemia (10 min) did not modify proteinuria. CKD induced by moderate ischemia was characterized by renal hypertrophy and tubulointerstitial fibrosis. These effects were associated with activation of the transforming growth factor β (TGFβ) signaling pathway and up-regulation of endothelin receptor A (ETA) and alpha smooth muscle actin (αSMA). Spironolactone treatment immediately or 1.5-h after the ischemic insult prevented the onset of these disorders. Our results show that moderate ischemic insult leads to long-term structural and molecular changes that may compromise renal function in later stages. Additionally, we demonstrate that spironolactone administration after mild ischemia prevents this detrimental effect.

No MeSH data available.


Related in: MedlinePlus