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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

Abundance of arginase-2 mRNA is increased in kidneys of diabetic Ins2Akita mice. A: RT-PCR was performed on RNA isolated from mouse kidney. GAPDH mRNA was used as an internal control for all RNA samples. Liver was used as a positive control for expression of arginase-1. B: Quantitative RT-PCR was performed on kidney RNA isolated at 14 weeks of age. Arginase-2 mRNA levels were normalized to GAPDH mRNA and expressed relative to levels in control DBA mice (set at 100%).
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Figure 2: Abundance of arginase-2 mRNA is increased in kidneys of diabetic Ins2Akita mice. A: RT-PCR was performed on RNA isolated from mouse kidney. GAPDH mRNA was used as an internal control for all RNA samples. Liver was used as a positive control for expression of arginase-1. B: Quantitative RT-PCR was performed on kidney RNA isolated at 14 weeks of age. Arginase-2 mRNA levels were normalized to GAPDH mRNA and expressed relative to levels in control DBA mice (set at 100%).

Mentions: We assessed whether both arginases are expressed in the kidneys under normal and diabetes conditions. Arginase-2, but not arginase-1, mRNA was detectable in the kidney (Fig. 2A). This result supports the view that the effect of BEC in the kidney is mainly mediated via inhibition of arginase-2. Both vehicle-treated and BEC-treated Ins2Akita mice had increased arginase-2 mRNA levels (Fig. 2B). Thus, diabetes is associated with increased kidney arginase-2 expression. Although BEC inhibits arginase activity, it did not downregulate arginase-2 mRNA in diabetes.


Arginase-2 mediates diabetic renal injury.

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

Abundance of arginase-2 mRNA is increased in kidneys of diabetic Ins2Akita mice. A: RT-PCR was performed on RNA isolated from mouse kidney. GAPDH mRNA was used as an internal control for all RNA samples. Liver was used as a positive control for expression of arginase-1. B: Quantitative RT-PCR was performed on kidney RNA isolated at 14 weeks of age. Arginase-2 mRNA levels were normalized to GAPDH mRNA and expressed relative to levels in control DBA mice (set at 100%).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: Abundance of arginase-2 mRNA is increased in kidneys of diabetic Ins2Akita mice. A: RT-PCR was performed on RNA isolated from mouse kidney. GAPDH mRNA was used as an internal control for all RNA samples. Liver was used as a positive control for expression of arginase-1. B: Quantitative RT-PCR was performed on kidney RNA isolated at 14 weeks of age. Arginase-2 mRNA levels were normalized to GAPDH mRNA and expressed relative to levels in control DBA mice (set at 100%).
Mentions: We assessed whether both arginases are expressed in the kidneys under normal and diabetes conditions. Arginase-2, but not arginase-1, mRNA was detectable in the kidney (Fig. 2A). This result supports the view that the effect of BEC in the kidney is mainly mediated via inhibition of arginase-2. Both vehicle-treated and BEC-treated Ins2Akita mice had increased arginase-2 mRNA levels (Fig. 2B). Thus, diabetes is associated with increased kidney arginase-2 expression. Although BEC inhibits arginase activity, it did not downregulate arginase-2 mRNA in diabetes.

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