Arginase-2 mediates diabetic renal injury

Sidney M. Morris, Ting Gao, Timothy K. Cooper, Diane Kepka-Lenhart, Alaa S. Awad

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3015-3022
Number of pages8
JournalDiabetes
Volume60
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Arginase
Kidney
Wounds and Injuries
Streptozocin
Experimental Diabetes Mellitus
Albuminuria
Diabetic Nephropathies
Hyperargininemia
Renal Circulation
Blood Urea Nitrogen
Type 2 Diabetes Mellitus
Research Design
Macrophages
Pharmacology

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Morris, S. M., Gao, T., Cooper, T. K., Kepka-Lenhart, D., & Awad, A. S. (2011). Arginase-2 mediates diabetic renal injury. Diabetes, 60(11), 3015-3022. https://doi.org/10.2337/db11-0901
Morris, Sidney M. ; Gao, Ting ; Cooper, Timothy K. ; Kepka-Lenhart, Diane ; Awad, Alaa S. / Arginase-2 mediates diabetic renal injury. In: Diabetes. 2011 ; Vol. 60, No. 11. pp. 3015-3022.
@article{8ae408070d4b43ee98c147aac0c7f7f9,
title = "Arginase-2 mediates diabetic renal injury",
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.",
author = "Morris, {Sidney M.} and Ting Gao and Cooper, {Timothy K.} and Diane Kepka-Lenhart and Awad, {Alaa S.}",
year = "2011",
month = "11",
day = "1",
doi = "10.2337/db11-0901",
language = "English (US)",
volume = "60",
pages = "3015--3022",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "11",

}

Morris, SM, Gao, T, Cooper, TK, Kepka-Lenhart, D & Awad, AS 2011, 'Arginase-2 mediates diabetic renal injury', Diabetes, vol. 60, no. 11, pp. 3015-3022. https://doi.org/10.2337/db11-0901

Arginase-2 mediates diabetic renal injury. / Morris, Sidney M.; Gao, Ting; Cooper, Timothy K.; Kepka-Lenhart, Diane; Awad, Alaa S.

In: Diabetes, Vol. 60, No. 11, 01.11.2011, p. 3015-3022.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Arginase-2 mediates diabetic renal injury

AU - Morris, Sidney M.

AU - Gao, Ting

AU - Cooper, Timothy K.

AU - Kepka-Lenhart, Diane

AU - Awad, Alaa S.

PY - 2011/11/1

Y1 - 2011/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80755152815&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80755152815&partnerID=8YFLogxK

U2 - 10.2337/db11-0901

DO - 10.2337/db11-0901

M3 - Article

C2 - 21926276

AN - SCOPUS:80755152815

VL - 60

SP - 3015

EP - 3022

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 11

ER -

Morris SM, Gao T, Cooper TK, Kepka-Lenhart D, Awad AS. Arginase-2 mediates diabetic renal injury. Diabetes. 2011 Nov 1;60(11):3015-3022. https://doi.org/10.2337/db11-0901