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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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Related in: MedlinePlus

Arginase-2 deficiency prevents increases in UAE in STZ-diabetic mice. Urine was collected for measurement of UAER in wild-type and Arg2−/− mice before (week 0) and after weeks 6 and 18 of STZ-induced diabetes. Data are means ± SEM for n = 6–15 mice in each group. Open bars are wild-type mice and filled bars are Arg2−/− mice. *P < 0.05 vs. Arg2−/− at week 0. Values of blood glucose (BG) are also shown as means ± SEM for n = 6–15 mice in each group.
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Figure 6: Arginase-2 deficiency prevents increases in UAE in STZ-diabetic mice. Urine was collected for measurement of UAER in wild-type and Arg2−/− mice before (week 0) and after weeks 6 and 18 of STZ-induced diabetes. Data are means ± SEM for n = 6–15 mice in each group. Open bars are wild-type mice and filled bars are Arg2−/− mice. *P < 0.05 vs. Arg2−/− at week 0. Values of blood glucose (BG) are also shown as means ± SEM for n = 6–15 mice in each group.

Mentions: We next assessed whether a genetic lack of arginase-2 will mimic the changes observed in Ins2Akita mice after pharmacologic arginase inhibition. Wild-type and Arg2−/− mice were treated with STZ and killed at either 6 or 18 weeks after STZ-induced diabetes. Wild-type mice displayed a significant increase in UAE after 6 weeks and after 18 weeks of STZ-induced diabetes (Fig. 6). In contrast, the increase in UAE was significantly reduced in Arg2−/− mice in a similar manner to BEC treatment in Ins2Akita. It is noteworthy that arginase-2 deficiency did not alter hyperglycemia in the diabetic mice (Fig. 6).


Arginase-2 mediates diabetic renal injury.

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

Arginase-2 deficiency prevents increases in UAE in STZ-diabetic mice. Urine was collected for measurement of UAER in wild-type and Arg2−/− mice before (week 0) and after weeks 6 and 18 of STZ-induced diabetes. Data are means ± SEM for n = 6–15 mice in each group. Open bars are wild-type mice and filled bars are Arg2−/− mice. *P < 0.05 vs. Arg2−/− at week 0. Values of blood glucose (BG) are also shown as means ± SEM for n = 6–15 mice in each group.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Arginase-2 deficiency prevents increases in UAE in STZ-diabetic mice. Urine was collected for measurement of UAER in wild-type and Arg2−/− mice before (week 0) and after weeks 6 and 18 of STZ-induced diabetes. Data are means ± SEM for n = 6–15 mice in each group. Open bars are wild-type mice and filled bars are Arg2−/− mice. *P < 0.05 vs. Arg2−/− at week 0. Values of blood glucose (BG) are also shown as means ± SEM for n = 6–15 mice in each group.
Mentions: We next assessed whether a genetic lack of arginase-2 will mimic the changes observed in Ins2Akita mice after pharmacologic arginase inhibition. Wild-type and Arg2−/− mice were treated with STZ and killed at either 6 or 18 weeks after STZ-induced diabetes. Wild-type mice displayed a significant increase in UAE after 6 weeks and after 18 weeks of STZ-induced diabetes (Fig. 6). In contrast, the increase in UAE was significantly reduced in Arg2−/− mice in a similar manner to BEC treatment in Ins2Akita. It is noteworthy that arginase-2 deficiency did not alter hyperglycemia in the diabetic mice (Fig. 6).

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