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Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.

Wang F, Zhang G, Lu Z, Geurts AM, Usa K, Jacob HJ, Cowley AW, Wang N, Liang M - Kidney Int. (2015)

Bottom Line: Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects.We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery.Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

ABSTRACT
Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1(+/-) rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1(+/-) rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1(+/-) rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.

No MeSH data available.


Related in: MedlinePlus

SerpinC1 insufficiency blunted the increase in renal prostaglandin (PGI2) following ischemia/reperfusion injury (IRI) before significantly exacerbating tubular injury. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 3 h after reperfusion. (a) Renal cortical levels of prostaglandin F1α (PGF1α). (b) Tubule injury score. (c) Renal cortical levels of malondialdehyde (MDA). N=4–5. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
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fig7: SerpinC1 insufficiency blunted the increase in renal prostaglandin (PGI2) following ischemia/reperfusion injury (IRI) before significantly exacerbating tubular injury. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 3 h after reperfusion. (a) Renal cortical levels of prostaglandin F1α (PGF1α). (b) Tubule injury score. (c) Renal cortical levels of malondialdehyde (MDA). N=4–5. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.

Mentions: Renal levels of prostaglandin F1α (PGF1α), a stable metabolite of PGI2, increased in the wild-type group at 3 h after reperfusion. The early increase in PGF1α was significantly blunted in SperinC1+/− rats (Figure 7a). The blunting of the increase in PGF1α in SperinC1+/− rats occurred before any significant exacerbation of tubular injury or oxidative stress. The increases in tubular injury scores and renal levels of malondialdehyde, which were exacerbated in SperinC1+/− rats at 24 h after reperfusion, were similar between SperinC1+/− rats and their wild-type littermates at the 3 h time point (Figure 7b and c).


Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.

Wang F, Zhang G, Lu Z, Geurts AM, Usa K, Jacob HJ, Cowley AW, Wang N, Liang M - Kidney Int. (2015)

SerpinC1 insufficiency blunted the increase in renal prostaglandin (PGI2) following ischemia/reperfusion injury (IRI) before significantly exacerbating tubular injury. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 3 h after reperfusion. (a) Renal cortical levels of prostaglandin F1α (PGF1α). (b) Tubule injury score. (c) Renal cortical levels of malondialdehyde (MDA). N=4–5. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4589441&req=5

fig7: SerpinC1 insufficiency blunted the increase in renal prostaglandin (PGI2) following ischemia/reperfusion injury (IRI) before significantly exacerbating tubular injury. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 3 h after reperfusion. (a) Renal cortical levels of prostaglandin F1α (PGF1α). (b) Tubule injury score. (c) Renal cortical levels of malondialdehyde (MDA). N=4–5. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
Mentions: Renal levels of prostaglandin F1α (PGF1α), a stable metabolite of PGI2, increased in the wild-type group at 3 h after reperfusion. The early increase in PGF1α was significantly blunted in SperinC1+/− rats (Figure 7a). The blunting of the increase in PGF1α in SperinC1+/− rats occurred before any significant exacerbation of tubular injury or oxidative stress. The increases in tubular injury scores and renal levels of malondialdehyde, which were exacerbated in SperinC1+/− rats at 24 h after reperfusion, were similar between SperinC1+/− rats and their wild-type littermates at the 3 h time point (Figure 7b and c).

Bottom Line: Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects.We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery.Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

ABSTRACT
Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1(+/-) rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1(+/-) rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1(+/-) rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.

No MeSH data available.


Related in: MedlinePlus