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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

Tubulointerstitial fibrosis development after 9 months of renal ischemia. Representative light micrographs after Sirius red staining showing the presence of fibrosis (in red) from the A) Sham (n=4), C and D) ischemic untreated ischemic group (n=5), E and F) Sp0 (n=4) and G and H) Sp1.5 (n=4). B) The percentage of tubulointerstitial fibrosis in each of the five groups at the end of the 270-day experiment was quantified by morphometric analysis for sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). Original magnification: X100 (A, C, E, G) and X400 (D, F, H). *p<0,05 vs. all the groups.
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Figure 4: Tubulointerstitial fibrosis development after 9 months of renal ischemia. Representative light micrographs after Sirius red staining showing the presence of fibrosis (in red) from the A) Sham (n=4), C and D) ischemic untreated ischemic group (n=5), E and F) Sp0 (n=4) and G and H) Sp1.5 (n=4). B) The percentage of tubulointerstitial fibrosis in each of the five groups at the end of the 270-day experiment was quantified by morphometric analysis for sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). Original magnification: X100 (A, C, E, G) and X400 (D, F, H). *p<0,05 vs. all the groups.

Mentions: Figure 4 shows the representative microphotographs from kidney slides stained with Sirius red and the morphometric analysis of the various groups. The untreated ischemic group exhibited a significant area affected by tubulointerstitial fibrosis (Figure 4C-4D). In contrast, the spironolactone-treated groups showed practically no staining for Sirius red (Figure 4E-4H). These observations were confirmed by the morphometric analysis presented in Figure 4B.


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)

Tubulointerstitial fibrosis development after 9 months of renal ischemia. Representative light micrographs after Sirius red staining showing the presence of fibrosis (in red) from the A) Sham (n=4), C and D) ischemic untreated ischemic group (n=5), E and F) Sp0 (n=4) and G and H) Sp1.5 (n=4). B) The percentage of tubulointerstitial fibrosis in each of the five groups at the end of the 270-day experiment was quantified by morphometric analysis for sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). Original magnification: X100 (A, C, E, G) and X400 (D, F, H). *p<0,05 vs. all the groups.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Tubulointerstitial fibrosis development after 9 months of renal ischemia. Representative light micrographs after Sirius red staining showing the presence of fibrosis (in red) from the A) Sham (n=4), C and D) ischemic untreated ischemic group (n=5), E and F) Sp0 (n=4) and G and H) Sp1.5 (n=4). B) The percentage of tubulointerstitial fibrosis in each of the five groups at the end of the 270-day experiment was quantified by morphometric analysis for sham (white bars), untreated ischemic group (black bars), and spironolactone-treated groups (gray bars). Original magnification: X100 (A, C, E, G) and X400 (D, F, H). *p<0,05 vs. all the groups.
Mentions: Figure 4 shows the representative microphotographs from kidney slides stained with Sirius red and the morphometric analysis of the various groups. The untreated ischemic group exhibited a significant area affected by tubulointerstitial fibrosis (Figure 4C-4D). In contrast, the spironolactone-treated groups showed practically no staining for Sirius red (Figure 4E-4H). These observations were confirmed by the morphometric analysis presented in Figure 4B.

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