Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice

Young Sun Kang, Mi Hwa Lee, Hye Kyoung Song, Young Youl Hyun, Jin Joo Cha, Gang Jee Ko, Sung Hwan Kim, Ji Eun Lee, Jee Young Han, Dae-Ryong Cha

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background. Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals.Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).Results. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.Conclusions. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Original languageEnglish
Pages (from-to)1194-1204
Number of pages11
JournalNephrology Dialysis Transplantation
Volume26
Issue number4
DOIs
Publication statusPublished - 2011 Apr 1

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Diabetic Angiopathies
Insulin Resistance
Renin
Mesangial Cells
Cultured Cells
Cytokines
Blood Pressure
Lipids
aliskiren
Angiotensin Receptor Antagonists
Angiotensins
Diabetic Nephropathies
Left Ventricular Hypertrophy
Lipid Metabolism
Type 2 Diabetes Mellitus
Electrolytes
Blood Glucose
Adipose Tissue
Albumins
Creatinine

Keywords

  • aliskiren
  • diabetic complication
  • direct renin inhibitor
  • insulin resistance

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice. / Kang, Young Sun; Lee, Mi Hwa; Song, Hye Kyoung; Hyun, Young Youl; Cha, Jin Joo; Ko, Gang Jee; Kim, Sung Hwan; Lee, Ji Eun; Han, Jee Young; Cha, Dae-Ryong.

In: Nephrology Dialysis Transplantation, Vol. 26, No. 4, 01.04.2011, p. 1194-1204.

Research output: Contribution to journalArticle

Kang, Young Sun ; Lee, Mi Hwa ; Song, Hye Kyoung ; Hyun, Young Youl ; Cha, Jin Joo ; Ko, Gang Jee ; Kim, Sung Hwan ; Lee, Ji Eun ; Han, Jee Young ; Cha, Dae-Ryong. / Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice. In: Nephrology Dialysis Transplantation. 2011 ; Vol. 26, No. 4. pp. 1194-1204.
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AU - Lee, Mi Hwa

AU - Song, Hye Kyoung

AU - Hyun, Young Youl

AU - Cha, Jin Joo

AU - Ko, Gang Jee

AU - Kim, Sung Hwan

AU - Lee, Ji Eun

AU - Han, Jee Young

AU - Cha, Dae-Ryong

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N2 - Background. Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals.Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).Results. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.Conclusions. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

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