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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

Twenty minutes of bilateral renal I/R led to renal structural injury, which can be prevented by spironolactone administration. Representative images of periodic acid-Schiff (PAS)-stained sections from A) Sham (n=4), B) untreated ischemic group (n=5), C) Sp0 (n=4) and D) Sp1.5 (n=4) groups. The main effects observed were: Tubular dilation, tubular cast formation and glomerular sclerosis. Original magnification: X100. E) Glomerulosclerosis percentage and F) Ratio between kidney weight and body weight (KW/BW). *p<0,05 vs. all the groups.
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Figure 3: Twenty minutes of bilateral renal I/R led to renal structural injury, which can be prevented by spironolactone administration. Representative images of periodic acid-Schiff (PAS)-stained sections from A) Sham (n=4), B) untreated ischemic group (n=5), C) Sp0 (n=4) and D) Sp1.5 (n=4) groups. The main effects observed were: Tubular dilation, tubular cast formation and glomerular sclerosis. Original magnification: X100. E) Glomerulosclerosis percentage and F) Ratio between kidney weight and body weight (KW/BW). *p<0,05 vs. all the groups.

Mentions: Representative light microscopy sections from rat kidneys stained with periodic acid-Schiff are shown in Figure 3A-D. IR induced structural changes characterized by glomerular hypertrophy, glomerulosclerosis, and cast formation (Figure 3B). In contrast, the Sp0 and Sp1.5 groups exhibited glomerular and tubular architecture similar to those observed in sham-operated rats (Figure 3C-D). Accordingly, the untreated ischemic group exhibited an increase in the percentage of glomerulosclerosis (14.4%), which was not observed in rats treated with spironolactone (Figure 3E). Renal hypertrophy was evaluated by kidney weight. Despite similar body weights among the groups, the kidney weight and body weight ratio (KW/BW) was 40% higher in the IR group than in the sham operated group (0.0042 ± 0.0004 vs. 0.00291 ± 0.0001, p=0.03), as shown in Figure 3F. This renal hypertrophy was not observed in any of spironolactone-treated groups (0.0030 ± 0.0001 and 0.0032 ± 0.0001 for Sp0 and Sp1.5, respectively).


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)

Twenty minutes of bilateral renal I/R led to renal structural injury, which can be prevented by spironolactone administration. Representative images of periodic acid-Schiff (PAS)-stained sections from A) Sham (n=4), B) untreated ischemic group (n=5), C) Sp0 (n=4) and D) Sp1.5 (n=4) groups. The main effects observed were: Tubular dilation, tubular cast formation and glomerular sclerosis. Original magnification: X100. E) Glomerulosclerosis percentage and F) Ratio between kidney weight and body weight (KW/BW). *p<0,05 vs. all the groups.
© Copyright Policy
Related In: Results  -  Collection

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Figure 3: Twenty minutes of bilateral renal I/R led to renal structural injury, which can be prevented by spironolactone administration. Representative images of periodic acid-Schiff (PAS)-stained sections from A) Sham (n=4), B) untreated ischemic group (n=5), C) Sp0 (n=4) and D) Sp1.5 (n=4) groups. The main effects observed were: Tubular dilation, tubular cast formation and glomerular sclerosis. Original magnification: X100. E) Glomerulosclerosis percentage and F) Ratio between kidney weight and body weight (KW/BW). *p<0,05 vs. all the groups.
Mentions: Representative light microscopy sections from rat kidneys stained with periodic acid-Schiff are shown in Figure 3A-D. IR induced structural changes characterized by glomerular hypertrophy, glomerulosclerosis, and cast formation (Figure 3B). In contrast, the Sp0 and Sp1.5 groups exhibited glomerular and tubular architecture similar to those observed in sham-operated rats (Figure 3C-D). Accordingly, the untreated ischemic group exhibited an increase in the percentage of glomerulosclerosis (14.4%), which was not observed in rats treated with spironolactone (Figure 3E). Renal hypertrophy was evaluated by kidney weight. Despite similar body weights among the groups, the kidney weight and body weight ratio (KW/BW) was 40% higher in the IR group than in the sham operated group (0.0042 ± 0.0004 vs. 0.00291 ± 0.0001, p=0.03), as shown in Figure 3F. This renal hypertrophy was not observed in any of spironolactone-treated groups (0.0030 ± 0.0001 and 0.0032 ± 0.0001 for Sp0 and Sp1.5, respectively).

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