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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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Kidney arginase activity is induced and associated with a reduction in renal medullary blood flow in diabetic wild-type mice but not in diabetic Arg2−/− mice. A: Arginase activities were assayed in kidney lysates prepared at the indicated times after STZ-induced diabetes. Open bars are wild-type mice and filled bars are Arg2−/− mice. Results are means ± SEM for n = 3–6 mice in each group. B: Plasma samples were obtained from wild-type controls and from wild-type and Arg2−/− mice after 18 weeks of STZ-induced diabetes. Arginase activities and arginase-1 protein levels were determined as described in research design and methods. Plasma arginase activities are expressed as means ± SEM for each group of individual mice depicted in the Western blot. C: Renal medullary blood flow was measured after 6 weeks of STZ-induced diabetes. Open bars are normal mice and filled bars are diabetic mice. Results are means ± SEM for n = 6–10 mice in each group.
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Figure 7: Kidney arginase activity is induced and associated with a reduction in renal medullary blood flow in diabetic wild-type mice but not in diabetic Arg2−/− mice. A: Arginase activities were assayed in kidney lysates prepared at the indicated times after STZ-induced diabetes. Open bars are wild-type mice and filled bars are Arg2−/− mice. Results are means ± SEM for n = 3–6 mice in each group. B: Plasma samples were obtained from wild-type controls and from wild-type and Arg2−/− mice after 18 weeks of STZ-induced diabetes. Arginase activities and arginase-1 protein levels were determined as described in research design and methods. Plasma arginase activities are expressed as means ± SEM for each group of individual mice depicted in the Western blot. C: Renal medullary blood flow was measured after 6 weeks of STZ-induced diabetes. Open bars are normal mice and filled bars are diabetic mice. Results are means ± SEM for n = 6–10 mice in each group.

Mentions: Diabetes was associated with a significant increase in kidney arginase activity at 6 and 18 weeks in wild-type mice after STZ-induced diabetes (Fig. 7A). These data were confirmed in vehicle-treated Ins2Akita mice after 9 weeks of diabetes, with increased kidney arginase activity versus control mice (22 ± 1 vs. 12 ± 1 nmol/min/mg). In contrast, Arg2−/− mice had minimal kidney arginase activity at all time points, confirming previous studies showing that overall arginase activity in the kidney is due almost entirely to arginase-2 (27). The small amount of kidney arginase activity in Arg2−/− mice under normal and diabetes conditions may be due to kidney-resident leukocytes that express arginase-1 or to trace arginase-1 contamination from plasma.


Arginase-2 mediates diabetic renal injury.

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

Kidney arginase activity is induced and associated with a reduction in renal medullary blood flow in diabetic wild-type mice but not in diabetic Arg2−/− mice. A: Arginase activities were assayed in kidney lysates prepared at the indicated times after STZ-induced diabetes. Open bars are wild-type mice and filled bars are Arg2−/− mice. Results are means ± SEM for n = 3–6 mice in each group. B: Plasma samples were obtained from wild-type controls and from wild-type and Arg2−/− mice after 18 weeks of STZ-induced diabetes. Arginase activities and arginase-1 protein levels were determined as described in research design and methods. Plasma arginase activities are expressed as means ± SEM for each group of individual mice depicted in the Western blot. C: Renal medullary blood flow was measured after 6 weeks of STZ-induced diabetes. Open bars are normal mice and filled bars are diabetic mice. Results are means ± SEM for n = 6–10 mice in each group.
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Related In: Results  -  Collection

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

Figure 7: Kidney arginase activity is induced and associated with a reduction in renal medullary blood flow in diabetic wild-type mice but not in diabetic Arg2−/− mice. A: Arginase activities were assayed in kidney lysates prepared at the indicated times after STZ-induced diabetes. Open bars are wild-type mice and filled bars are Arg2−/− mice. Results are means ± SEM for n = 3–6 mice in each group. B: Plasma samples were obtained from wild-type controls and from wild-type and Arg2−/− mice after 18 weeks of STZ-induced diabetes. Arginase activities and arginase-1 protein levels were determined as described in research design and methods. Plasma arginase activities are expressed as means ± SEM for each group of individual mice depicted in the Western blot. C: Renal medullary blood flow was measured after 6 weeks of STZ-induced diabetes. Open bars are normal mice and filled bars are diabetic mice. Results are means ± SEM for n = 6–10 mice in each group.
Mentions: Diabetes was associated with a significant increase in kidney arginase activity at 6 and 18 weeks in wild-type mice after STZ-induced diabetes (Fig. 7A). These data were confirmed in vehicle-treated Ins2Akita mice after 9 weeks of diabetes, with increased kidney arginase activity versus control mice (22 ± 1 vs. 12 ± 1 nmol/min/mg). In contrast, Arg2−/− mice had minimal kidney arginase activity at all time points, confirming previous studies showing that overall arginase activity in the kidney is due almost entirely to arginase-2 (27). The small amount of kidney arginase activity in Arg2−/− mice under normal and diabetes conditions may be due to kidney-resident leukocytes that express arginase-1 or to trace arginase-1 contamination from plasma.

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