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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 histological changes in STZ-diabetic mice. Sections were stained with PAS, and all glomeruli were graded individually at 400× magnification. Images were taken with 100× (oil) objective with a total magnification of 1,000×. Images are representative of six to eight mice in each group. A: Representative PAS section from normal mouse showing morphologically normal glomerulus with delicate PAS-positive basement membranes and minimal PAS staining of mesangial matrix. Adjacent tubular basement membranes and brush-border stain PAS-positive as well. B: Representative PAS section from vehicle-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies 25–50% of the mesangial matrix within the tuft. C: Representative PAS section from BEC-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies <25% of the mesangial matrix. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 5: Arginase inhibition reduces histological changes in STZ-diabetic mice. Sections were stained with PAS, and all glomeruli were graded individually at 400× magnification. Images were taken with 100× (oil) objective with a total magnification of 1,000×. Images are representative of six to eight mice in each group. A: Representative PAS section from normal mouse showing morphologically normal glomerulus with delicate PAS-positive basement membranes and minimal PAS staining of mesangial matrix. Adjacent tubular basement membranes and brush-border stain PAS-positive as well. B: Representative PAS section from vehicle-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies 25–50% of the mesangial matrix within the tuft. C: Representative PAS section from BEC-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies <25% of the mesangial matrix. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: PAS staining of kidney sections showed increased glomerular cellularity and mesangial expansion (score, 1.9 ± 0.05 vs. 1.1 ± 0.09; P < 0.005) after 6 weeks of diabetes in vehicle-treated, STZ-diabetic mice versus controls (Fig. 5A and B). Inhibition of arginases in STZ-induced diabetic mice exhibited significantly reduced glomerular changes (scores, 1.6 ± 0.08; P < 0.05) compared with vehicle-treated, STZ-induced mice (Fig. 5C). As expected for a period of induced diabetes of only 6 weeks, there was little or no indication of fibrosis by Masson’s trichrome or the periodic acid methenamine silver (aka Jones stain) staining, which was not detectably different between any of the groups (data not shown).


Arginase-2 mediates diabetic renal injury.

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

Arginase inhibition reduces histological changes in STZ-diabetic mice. Sections were stained with PAS, and all glomeruli were graded individually at 400× magnification. Images were taken with 100× (oil) objective with a total magnification of 1,000×. Images are representative of six to eight mice in each group. A: Representative PAS section from normal mouse showing morphologically normal glomerulus with delicate PAS-positive basement membranes and minimal PAS staining of mesangial matrix. Adjacent tubular basement membranes and brush-border stain PAS-positive as well. B: Representative PAS section from vehicle-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies 25–50% of the mesangial matrix within the tuft. C: Representative PAS section from BEC-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies <25% of the mesangial matrix. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 5: Arginase inhibition reduces histological changes in STZ-diabetic mice. Sections were stained with PAS, and all glomeruli were graded individually at 400× magnification. Images were taken with 100× (oil) objective with a total magnification of 1,000×. Images are representative of six to eight mice in each group. A: Representative PAS section from normal mouse showing morphologically normal glomerulus with delicate PAS-positive basement membranes and minimal PAS staining of mesangial matrix. Adjacent tubular basement membranes and brush-border stain PAS-positive as well. B: Representative PAS section from vehicle-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies 25–50% of the mesangial matrix within the tuft. C: Representative PAS section from BEC-treated, STZ-diabetic mouse showing glomerular expansion in which PAS-positive material occupies <25% of the mesangial matrix. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: PAS staining of kidney sections showed increased glomerular cellularity and mesangial expansion (score, 1.9 ± 0.05 vs. 1.1 ± 0.09; P < 0.005) after 6 weeks of diabetes in vehicle-treated, STZ-diabetic mice versus controls (Fig. 5A and B). Inhibition of arginases in STZ-induced diabetic mice exhibited significantly reduced glomerular changes (scores, 1.6 ± 0.08; P < 0.05) compared with vehicle-treated, STZ-induced mice (Fig. 5C). As expected for a period of induced diabetes of only 6 weeks, there was little or no indication of fibrosis by Masson’s trichrome or the periodic acid methenamine silver (aka Jones stain) staining, which was not detectably different between any of the groups (data not shown).

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