L-citrulline protects from kidney damage in type 1 diabetic mice

Maritza Josefina Romero Lucas, Lin Yao, Supriya Sridhar, Anil Bhatta, Huijuan Dou, Ganesan Ramesh, Michael W Brands, David M. Pollock, Ruth B Caldwell, Stephen D. Cederbaum, C. Alvin Head, Zsolt Bagi, Rudolf Lucas, Robert William Caldwell

Research output: Contribution to journalArticle

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Abstract

Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of L-arginine (L-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. L-Citrulline (L-cit) supplementation not only increases L-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of L-arg, in the vasculature. Aims: To investigate whether L-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received L-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and L-cit-treated STZ-rats were evaluated. Results: L-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, L-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. L-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, L-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. Conclusion: L-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.

Original languageEnglish (US)
Article numberArticle 480
JournalFrontiers in immunology
Volume4
Issue numberDEC
DOIs
StatePublished - Dec 1 2013

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Citrulline
Arginase
Kidney
Streptozocin
Knockout Mice
Anti-Inflammatory Agents
Nitric Oxide Synthase Type III
Diabetic Nephropathies
Type 1 Diabetes Mellitus
Interleukin-10
Hypertrophy
Wild Animals
Albuminuria
Blood Urea Nitrogen
Nephrons
Interleukin-12
Interleukin-1
Drinking Water
Chronic Kidney Failure
Blood Vessels

Keywords

  • Arginase
  • Diabetic nephropathy
  • Glomerulosclerosis
  • IL-10
  • L-citrulline

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

L-citrulline protects from kidney damage in type 1 diabetic mice. / Romero Lucas, Maritza Josefina; Yao, Lin; Sridhar, Supriya; Bhatta, Anil; Dou, Huijuan; Ramesh, Ganesan; Brands, Michael W; Pollock, David M.; Caldwell, Ruth B; Cederbaum, Stephen D.; Alvin Head, C.; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Robert William.

In: Frontiers in immunology, Vol. 4, No. DEC, Article 480, 01.12.2013.

Research output: Contribution to journalArticle

Romero Lucas, MJ, Yao, L, Sridhar, S, Bhatta, A, Dou, H, Ramesh, G, Brands, MW, Pollock, DM, Caldwell, RB, Cederbaum, SD, Alvin Head, C, Bagi, Z, Lucas, R & Caldwell, RW 2013, 'L-citrulline protects from kidney damage in type 1 diabetic mice', Frontiers in immunology, vol. 4, no. DEC, Article 480. https://doi.org/10.3389/fimmu.2013.00480
Romero Lucas, Maritza Josefina ; Yao, Lin ; Sridhar, Supriya ; Bhatta, Anil ; Dou, Huijuan ; Ramesh, Ganesan ; Brands, Michael W ; Pollock, David M. ; Caldwell, Ruth B ; Cederbaum, Stephen D. ; Alvin Head, C. ; Bagi, Zsolt ; Lucas, Rudolf ; Caldwell, Robert William. / L-citrulline protects from kidney damage in type 1 diabetic mice. In: Frontiers in immunology. 2013 ; Vol. 4, No. DEC.
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abstract = "Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of L-arginine (L-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. L-Citrulline (L-cit) supplementation not only increases L-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of L-arg, in the vasculature. Aims: To investigate whether L-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received L-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and L-cit-treated STZ-rats were evaluated. Results: L-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, L-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. L-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, L-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. Conclusion: L-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.",
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T1 - L-citrulline protects from kidney damage in type 1 diabetic mice

AU - Romero Lucas, Maritza Josefina

AU - Yao, Lin

AU - Sridhar, Supriya

AU - Bhatta, Anil

AU - Dou, Huijuan

AU - Ramesh, Ganesan

AU - Brands, Michael W

AU - Pollock, David M.

AU - Caldwell, Ruth B

AU - Cederbaum, Stephen D.

AU - Alvin Head, C.

AU - Bagi, Zsolt

AU - Lucas, Rudolf

AU - Caldwell, Robert William

PY - 2013/12/1

Y1 - 2013/12/1

N2 - Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of L-arginine (L-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. L-Citrulline (L-cit) supplementation not only increases L-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of L-arg, in the vasculature. Aims: To investigate whether L-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received L-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and L-cit-treated STZ-rats were evaluated. Results: L-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, L-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. L-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, L-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. Conclusion: L-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.

AB - Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of L-arginine (L-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. L-Citrulline (L-cit) supplementation not only increases L-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of L-arg, in the vasculature. Aims: To investigate whether L-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. Methods: STZ-C57BL6 mice received L-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and L-cit-treated STZ-rats were evaluated. Results: L-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, L-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. L-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, L-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells. Conclusion: L-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.

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