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

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.

• Authors: 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
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 26 Issue 4 Pg. 1194-204 (Apr 2011) ISSN: 1460-2385 [Electronic] England
• PMID: 20921292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Biomarkers, Tumor
• Blood Glucose
• Fumarates
• Insulin
• RNA, Messenger
• aliskiren
• Renin

Topics

• Amides (therapeutic use)
• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Blood Glucose (drug effects, metabolism)
• Blood Pressure (drug effects)
• Blotting, Western
• Body Weight (drug effects)
• Cells, Cultured
• Diabetes Complications (prevention & control)
• Diabetes Mellitus, Experimental (physiopathology)
• Diabetes Mellitus, Type 2 (physiopathology)
• Diabetic Angiopathies (prevention & control)
• Diabetic Nephropathies (prevention & control)
• Fumarates (therapeutic use)
• Gene Expression Profiling
• Humans
• Immunoenzyme Techniques
• Insulin (metabolism)
• Insulin Resistance
• Male
• Mesangial Cells (cytology, drug effects, metabolism)
• Mice
• Mice, Mutant Strains
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (genetics)
• Renin (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction