Limits...
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 did not result in renal thrombosis. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Unflushed kidneys were harvested 24 h after reperfusion. (a) Several representative images of Masson trichrome staining are shown for a broad region of the kidney (left, × 100) and glomerular capillary, arteriole, and small veins (right, × 400). Red blood cells were observed in the blood vessels, consistent with the kidneys not being flushed before harvesting. Thrombi were not observed. (b) Plasma levels of fibrinogen. (c) Plasma levels of fibrinogen degradation products (FDPs). N=6. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4589441&req=5

fig3: SerpinC1 insufficiency did not result in renal thrombosis. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Unflushed kidneys were harvested 24 h after reperfusion. (a) Several representative images of Masson trichrome staining are shown for a broad region of the kidney (left, × 100) and glomerular capillary, arteriole, and small veins (right, × 400). Red blood cells were observed in the blood vessels, consistent with the kidneys not being flushed before harvesting. Thrombi were not observed. (b) Plasma levels of fibrinogen. (c) Plasma levels of fibrinogen degradation products (FDPs). N=6. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.

Mentions: Intuitively, we suspected that SerpinC1 insufficiency might exacerbate renal IRI by causing renal thrombosis. We examined trichrome staining of sections of unflushed kidneys from SerpinC1+/− rats and wild-type littermates and looked for signs of thrombosis in the renal vasculature. No sign of thrombosis was observed in the renal vasculature of either genotype following the IRI (Figure 3a). Plasma levels of fibrinogen and fibrinogen degradation products were not significantly different between wild-type and SerpinC1+/− rats before or after IRI (Figure 3b and c), consistent with the lack of overt thrombosis in SerpinC1+/− rats.


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 did not result in renal thrombosis. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Unflushed kidneys were harvested 24 h after reperfusion. (a) Several representative images of Masson trichrome staining are shown for a broad region of the kidney (left, × 100) and glomerular capillary, arteriole, and small veins (right, × 400). Red blood cells were observed in the blood vessels, consistent with the kidneys not being flushed before harvesting. Thrombi were not observed. (b) Plasma levels of fibrinogen. (c) Plasma levels of fibrinogen degradation products (FDPs). 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

fig3: SerpinC1 insufficiency did not result in renal thrombosis. Rats were subjected to uninephrectomy and 30 min of warm ischemia of the remaining kidney. Unflushed kidneys were harvested 24 h after reperfusion. (a) Several representative images of Masson trichrome staining are shown for a broad region of the kidney (left, × 100) and glomerular capillary, arteriole, and small veins (right, × 400). Red blood cells were observed in the blood vessels, consistent with the kidneys not being flushed before harvesting. Thrombi were not observed. (b) Plasma levels of fibrinogen. (c) Plasma levels of fibrinogen degradation products (FDPs). N=6. Het, SerpinC1+/− rat; IR, ischemia/reperfusion; Sham, sham operated; WT, wild-type littermate.
Mentions: Intuitively, we suspected that SerpinC1 insufficiency might exacerbate renal IRI by causing renal thrombosis. We examined trichrome staining of sections of unflushed kidneys from SerpinC1+/− rats and wild-type littermates and looked for signs of thrombosis in the renal vasculature. No sign of thrombosis was observed in the renal vasculature of either genotype following the IRI (Figure 3a). Plasma levels of fibrinogen and fibrinogen degradation products were not significantly different between wild-type and SerpinC1+/− rats before or after IRI (Figure 3b and c), consistent with the lack of overt thrombosis in SerpinC1+/− rats.

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