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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 increased renal tubular apoptosis in rats with ischemia/reperfusion injury (IRI). Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 24 h after reperfusion. (a) Representative images of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (× 400, left) and overlays with 4',6-diamidino-2-phenylindole (DAPI) staining (right). (b) Quantatitive analysis. N=6. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
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fig5: SerpinC1 insufficiency increased renal tubular apoptosis in rats with ischemia/reperfusion injury (IRI). Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 24 h after reperfusion. (a) Representative images of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (× 400, left) and overlays with 4',6-diamidino-2-phenylindole (DAPI) staining (right). (b) Quantatitive analysis. N=6. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.

Mentions: The renal IRI was accompanied by increased renal oxidative stress, tubular apoptosis, and macrophage infiltration in wild-type littermates, assessed by measurements of renal levels of malondialdehyde, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)–positive cells, and F4/80-positive cells, respectively (Figures 4, 5, 6). Renal oxidative stress, tubular apoptosis, and macrophage infiltration following IRI were significantly exacerbated in SperinC1+/− rats (Figures 4,5,6).


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 increased renal tubular apoptosis in rats with ischemia/reperfusion injury (IRI). Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 24 h after reperfusion. (a) Representative images of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (× 400, left) and overlays with 4',6-diamidino-2-phenylindole (DAPI) staining (right). (b) Quantatitive analysis. N=6. 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

fig5: SerpinC1 insufficiency increased renal tubular apoptosis in rats with ischemia/reperfusion injury (IRI). Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Kidneys were harvested 24 h after reperfusion. (a) Representative images of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (× 400, left) and overlays with 4',6-diamidino-2-phenylindole (DAPI) staining (right). (b) Quantatitive analysis. N=6. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
Mentions: The renal IRI was accompanied by increased renal oxidative stress, tubular apoptosis, and macrophage infiltration in wild-type littermates, assessed by measurements of renal levels of malondialdehyde, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)–positive cells, and F4/80-positive cells, respectively (Figures 4, 5, 6). Renal oxidative stress, tubular apoptosis, and macrophage infiltration following IRI were significantly exacerbated in SperinC1+/− rats (Figures 4,5,6).

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