Limits...
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.

Show MeSH

Related in: MedlinePlus

Arginase inhibition reduces increases in UAE in STZ-diabetic mice. DBA mice were given multiple intraperitoneal injections of vehicle or STZ as described in research design and methods. Mice were treated with BEC (2.3 mg/kg/day) or vehicle via osmotic minipump for 6 weeks, at which time urine was collected for measurement of UAE. Blood glucose (BG) levels and UAER values are means ± SEM for n = 5–6 mice in each group. *P < 0.05; **P < 0.0001, compared with normal; #P < 0.05, compared with diabetes + vehicle group.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198072&req=5

Figure 4: Arginase inhibition reduces increases in UAE in STZ-diabetic mice. DBA mice were given multiple intraperitoneal injections of vehicle or STZ as described in research design and methods. Mice were treated with BEC (2.3 mg/kg/day) or vehicle via osmotic minipump for 6 weeks, at which time urine was collected for measurement of UAE. Blood glucose (BG) levels and UAER values are means ± SEM for n = 5–6 mice in each group. *P < 0.05; **P < 0.0001, compared with normal; #P < 0.05, compared with diabetes + vehicle group.

Mentions: To determine whether the effect of arginase inhibition is specific to Ins2Akita mice, we used another type 1 diabetic mouse model (DBA/2J) using STZ to induce diabetes for a 6-week study period. We measured 24-h UAE as indicators of renal injury with and without BEC treatment. Vehicle-treated, STZ-induced diabetic mice had a significant increase in albuminuria compared with controls after 6 weeks, an effect that was significantly reduced with BEC treatment in diabetic mice despite comparable blood glucose levels (Fig. 4). We also show an increase in kidney macrophage recruitment using Mac-2 staining in vehicle-treated, STZ-induced diabetic mice (1.9 ± 0.1 macrophages/glomerulus; P < 0.0001) compared with control (0.6 ± 0.05 macrophages/glomerulus). In contrast, BEC-treated, STZ-diabetic mice had a significant reduction in glomerular macrophage recruitment (1.2 ± 0.06 macrophages/glomerulus; P < 0.0001) compared with vehicle-treated STZ-diabetic mice.


Arginase-2 mediates diabetic renal injury.

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

Arginase inhibition reduces increases in UAE in STZ-diabetic mice. DBA mice were given multiple intraperitoneal injections of vehicle or STZ as described in research design and methods. Mice were treated with BEC (2.3 mg/kg/day) or vehicle via osmotic minipump for 6 weeks, at which time urine was collected for measurement of UAE. Blood glucose (BG) levels and UAER values are means ± SEM for n = 5–6 mice in each group. *P < 0.05; **P < 0.0001, compared with normal; #P < 0.05, compared with diabetes + vehicle group.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 4: Arginase inhibition reduces increases in UAE in STZ-diabetic mice. DBA mice were given multiple intraperitoneal injections of vehicle or STZ as described in research design and methods. Mice were treated with BEC (2.3 mg/kg/day) or vehicle via osmotic minipump for 6 weeks, at which time urine was collected for measurement of UAE. Blood glucose (BG) levels and UAER values are means ± SEM for n = 5–6 mice in each group. *P < 0.05; **P < 0.0001, compared with normal; #P < 0.05, compared with diabetes + vehicle group.
Mentions: To determine whether the effect of arginase inhibition is specific to Ins2Akita mice, we used another type 1 diabetic mouse model (DBA/2J) using STZ to induce diabetes for a 6-week study period. We measured 24-h UAE as indicators of renal injury with and without BEC treatment. Vehicle-treated, STZ-induced diabetic mice had a significant increase in albuminuria compared with controls after 6 weeks, an effect that was significantly reduced with BEC treatment in diabetic mice despite comparable blood glucose levels (Fig. 4). We also show an increase in kidney macrophage recruitment using Mac-2 staining in vehicle-treated, STZ-induced diabetic mice (1.9 ± 0.1 macrophages/glomerulus; P < 0.0001) compared with control (0.6 ± 0.05 macrophages/glomerulus). In contrast, BEC-treated, STZ-diabetic mice had a significant reduction in glomerular macrophage recruitment (1.2 ± 0.06 macrophages/glomerulus; P < 0.0001) compared with vehicle-treated STZ-diabetic mice.

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