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Arginase-2 mediates diabetic renal injury.

Morris SM, Gao T, Cooper TK, Kepka-Lenhart D, Awad AS - Diabetes (2011)

Bottom Line: In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions.The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2(-/-) mice.These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

ABSTRACT

Objective: To determine 1) whether renal arginase activity or expression is increased in diabetes and 2) whether arginase plays a role in development of diabetic nephropathy (DN).

Research design and methods: The impact of arginase activity and expression on renal damage was evaluated in spontaneously diabetic Ins2(Akita) mice and in streptozotocin (STZ)-induced diabetic Dilute Brown Agouti (DBA) and arginase-2-deficient mice (Arg2(-/-)).

Results: Pharmacological blockade or genetic deficiency of arginase-2 conferred kidney protection in Ins2(Akita) mice or STZ-induced diabetic renal injury. Blocking arginases using S-(2-boronoethyl)-L-cysteine for 9 weeks in Ins2(Akita) mice or 6 weeks in STZ-induced diabetic DBA mice significantly attenuated albuminuria, the increase in blood urea nitrogen, histopathological changes, and kidney macrophage recruitment compared with vehicle-treated Ins2(Akita) mice. Furthermore, kidney arginase-2 expression increased in Ins2(Akita) mice compared with control. In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions. Arg2(-/-) mice mimicked arginase blockade by reducing albuminuria after 6 and 18 weeks of STZ-induced diabetes. In wild-type mice, kidney arginase activity increased significantly after 6 and 18 weeks of STZ-induced diabetes but remained very low in STZ-diabetic Arg2(-/-) mice. The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2(-/-) mice.

Conclusions: These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.

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Arginase inhibition reduces macrophage infiltration in diabetic Ins2Akita mice. A: Mac-2–positive macrophages in glomeruli were identified by immunohistochemical staining at 14 weeks of age in wild-type DBA mice treated with vehicle, Ins2Akita mice treated with vehicle, wild-type mice treated with BEC, and Ins2Akita mice treated with BEC. Images are representative of 20 fields from six to eight mice in each group. B: Experimental groups were as described in (A). Kidneys were harvested at 14 weeks of age and processed for fluorescence-activated cell sorter analysis as described in research design and methods. Macrophages were identified as CD11bhighF4/80low. Graphs show representative contour plots. Numbers of CD11bhighF4/80low macrophages per gram kidney tissue are expressed as means ± SEM for n = 6–8 mice in each group. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: Arginase inhibition reduces macrophage infiltration in diabetic Ins2Akita mice. A: Mac-2–positive macrophages in glomeruli were identified by immunohistochemical staining at 14 weeks of age in wild-type DBA mice treated with vehicle, Ins2Akita mice treated with vehicle, wild-type mice treated with BEC, and Ins2Akita mice treated with BEC. Images are representative of 20 fields from six to eight mice in each group. B: Experimental groups were as described in (A). Kidneys were harvested at 14 weeks of age and processed for fluorescence-activated cell sorter analysis as described in research design and methods. Macrophages were identified as CD11bhighF4/80low. Graphs show representative contour plots. Numbers of CD11bhighF4/80low macrophages per gram kidney tissue are expressed as means ± SEM for n = 6–8 mice in each group. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: To determine whether arginase is critical for macrophage infiltration in DN, we show the distribution and quantitation of macrophages in kidneys by immunohistochemistry (Mac-2–positive macrophages) (Fig. 3A). Vehicle-treated Ins2Akita mice showed significant increases in glomerular macrophages (2.95 ± 0.14 macrophages/glomerulus; P < 0.0001) compared with vehicle-treated control (0.34 ± 0.04 macrophages/glomerulus). Both BEC-treated control and Ins2Akita mice had significantly reduced glomerular macrophage recruitment (0.29 ± 0.03 and 0.9 ± 0.14 macrophages/glomerulus; P < 0.0001), respectively, compared with vehicle-treated Ins2Akita mice at 14 weeks of age.


Arginase-2 mediates diabetic renal injury.

Morris SM, Gao T, Cooper TK, Kepka-Lenhart D, Awad AS - Diabetes (2011)

Arginase inhibition reduces macrophage infiltration in diabetic Ins2Akita mice. A: Mac-2–positive macrophages in glomeruli were identified by immunohistochemical staining at 14 weeks of age in wild-type DBA mice treated with vehicle, Ins2Akita mice treated with vehicle, wild-type mice treated with BEC, and Ins2Akita mice treated with BEC. Images are representative of 20 fields from six to eight mice in each group. B: Experimental groups were as described in (A). Kidneys were harvested at 14 weeks of age and processed for fluorescence-activated cell sorter analysis as described in research design and methods. Macrophages were identified as CD11bhighF4/80low. Graphs show representative contour plots. Numbers of CD11bhighF4/80low macrophages per gram kidney tissue are expressed as means ± SEM for n = 6–8 mice in each group. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198072&req=5

Figure 3: Arginase inhibition reduces macrophage infiltration in diabetic Ins2Akita mice. A: Mac-2–positive macrophages in glomeruli were identified by immunohistochemical staining at 14 weeks of age in wild-type DBA mice treated with vehicle, Ins2Akita mice treated with vehicle, wild-type mice treated with BEC, and Ins2Akita mice treated with BEC. Images are representative of 20 fields from six to eight mice in each group. B: Experimental groups were as described in (A). Kidneys were harvested at 14 weeks of age and processed for fluorescence-activated cell sorter analysis as described in research design and methods. Macrophages were identified as CD11bhighF4/80low. Graphs show representative contour plots. Numbers of CD11bhighF4/80low macrophages per gram kidney tissue are expressed as means ± SEM for n = 6–8 mice in each group. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: To determine whether arginase is critical for macrophage infiltration in DN, we show the distribution and quantitation of macrophages in kidneys by immunohistochemistry (Mac-2–positive macrophages) (Fig. 3A). Vehicle-treated Ins2Akita mice showed significant increases in glomerular macrophages (2.95 ± 0.14 macrophages/glomerulus; P < 0.0001) compared with vehicle-treated control (0.34 ± 0.04 macrophages/glomerulus). Both BEC-treated control and Ins2Akita mice had significantly reduced glomerular macrophage recruitment (0.29 ± 0.03 and 0.9 ± 0.14 macrophages/glomerulus; P < 0.0001), respectively, compared with vehicle-treated Ins2Akita mice at 14 weeks of age.

Bottom Line: In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions.The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2(-/-) mice.These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

ABSTRACT

Objective: To determine 1) whether renal arginase activity or expression is increased in diabetes and 2) whether arginase plays a role in development of diabetic nephropathy (DN).

Research design and methods: The impact of arginase activity and expression on renal damage was evaluated in spontaneously diabetic Ins2(Akita) mice and in streptozotocin (STZ)-induced diabetic Dilute Brown Agouti (DBA) and arginase-2-deficient mice (Arg2(-/-)).

Results: Pharmacological blockade or genetic deficiency of arginase-2 conferred kidney protection in Ins2(Akita) mice or STZ-induced diabetic renal injury. Blocking arginases using S-(2-boronoethyl)-L-cysteine for 9 weeks in Ins2(Akita) mice or 6 weeks in STZ-induced diabetic DBA mice significantly attenuated albuminuria, the increase in blood urea nitrogen, histopathological changes, and kidney macrophage recruitment compared with vehicle-treated Ins2(Akita) mice. Furthermore, kidney arginase-2 expression increased in Ins2(Akita) mice compared with control. In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions. Arg2(-/-) mice mimicked arginase blockade by reducing albuminuria after 6 and 18 weeks of STZ-induced diabetes. In wild-type mice, kidney arginase activity increased significantly after 6 and 18 weeks of STZ-induced diabetes but remained very low in STZ-diabetic Arg2(-/-) mice. The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2(-/-) mice.

Conclusions: These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.

Show MeSH
Related in: MedlinePlus