Local delivery of angiotensin II receptor blockers into the kidney passively attenuates inflammatory reactions during the early phases of streptozotocin-induced diabetic nephropathy through inhibition of calpain activity

Fadia Kamal, Nadezhda Yanakieva-Georgieva, Honglan Piao, Tetsuo Morioka, Takashi Oite

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background/Aims: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. Methods and Results: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-κB, as shown by an increase in the expression of the p65 subunit of NF-κB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. Conclusion: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.

Original languageEnglish (US)
JournalNephron - Experimental Nephrology
Volume115
Issue number3
DOIs
StatePublished - Jul 1 2010

Fingerprint

Calpain
Angiotensin Receptor Antagonists
Diabetic Nephropathies
Streptozocin
Kidney
Renin-Angiotensin System
Spectrin
Angiotensin Type 1 Receptor
Nitric Oxide Synthase Type III
Blood Urea Nitrogen
Blood Proteins
Monocytes
Cytoplasm
Proteins
Endothelial Cells
Epithelial Cells
Macrophages
Staining and Labeling
Inflammation
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Physiology
  • Genetics
  • Nephrology

Cite this

@article{a9d9a04a3a4d4f068b1c8c21d7ef4343,
title = "Local delivery of angiotensin II receptor blockers into the kidney passively attenuates inflammatory reactions during the early phases of streptozotocin-induced diabetic nephropathy through inhibition of calpain activity",
abstract = "Background/Aims: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. Methods and Results: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-κB, as shown by an increase in the expression of the p65 subunit of NF-κB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. Conclusion: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.",
author = "Fadia Kamal and Nadezhda Yanakieva-Georgieva and Honglan Piao and Tetsuo Morioka and Takashi Oite",
year = "2010",
month = "7",
day = "1",
doi = "10.1159/000313832",
language = "English (US)",
volume = "115",
journal = "Experimental Nephrology",
issn = "0028-2766",
publisher = "S. Karger AG",
number = "3",

}

TY - JOUR

T1 - Local delivery of angiotensin II receptor blockers into the kidney passively attenuates inflammatory reactions during the early phases of streptozotocin-induced diabetic nephropathy through inhibition of calpain activity

AU - Kamal, Fadia

AU - Yanakieva-Georgieva, Nadezhda

AU - Piao, Honglan

AU - Morioka, Tetsuo

AU - Oite, Takashi

PY - 2010/7/1

Y1 - 2010/7/1

N2 - Background/Aims: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. Methods and Results: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-κB, as shown by an increase in the expression of the p65 subunit of NF-κB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. Conclusion: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.

AB - Background/Aims: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. Methods and Results: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-κB, as shown by an increase in the expression of the p65 subunit of NF-κB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. Conclusion: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.

UR - http://www.scopus.com/inward/record.url?scp=77951215973&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951215973&partnerID=8YFLogxK

U2 - 10.1159/000313832

DO - 10.1159/000313832

M3 - Article

C2 - 20424485

AN - SCOPUS:77951215973

VL - 115

JO - Experimental Nephrology

JF - Experimental Nephrology

SN - 0028-2766

IS - 3

ER -