1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the...

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Diabetic nephropathy involves renal injury mediated by the renin-angiotensin system (RAS).
• 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is known to protect kidneys by suppressing RAS.
• While its effect on renin is understood, the mechanism of vitamin D's regulation of angiotensinogen (AGT) is unclear.

Purpose of the Study:

• To elucidate the mechanism by which 1,25(OH)(2)D(3) regulates angiotensinogen (AGT) expression.
• To investigate the role of the NF-kappaB pathway in high glucose-induced AGT expression.
• To determine the interaction between 1,25(OH)(2)D(3) and NF-kappaB in regulating AGT.

Main Methods:

• Cell culture experiments using mesangial cells and podocytes exposed to high glucose.
• Inhibition studies using 1,25(OH)(2)D(3) and NF-kappaB inhibitors.
• Luciferase reporter assays, Electrophoretic Mobility Shift Assays (EMSA), and Chromatin Immunoprecipitation (ChIP) assays.
• In vivo studies using vitamin D receptor knockout mice and diabetic mice treated with a vitamin D analog.

Main Results:

• High glucose significantly increased AGT expression in mesangial cells and podocytes.
• 1,25(OH)(2)D(3) and NF-kappaB inhibitors suppressed high glucose-induced AGT expression.
• 1,25(OH)(2)D(3) inhibited NF-kappaB activity and blocked p65/p50 binding to the AGT gene promoter.
• Vitamin D receptor deficiency increased kidney AGT mRNA, and vitamin D analog treatment suppressed AGT induction in diabetic mice.

Conclusions:

• 1,25(OH)(2)D(3) suppresses high glucose-induced AGT expression through the NF-kappaB-mediated pathway.
• This mechanism involves blocking the binding of NF-kappaB to a specific site on the AGT gene promoter.
• These findings highlight a potential therapeutic role for vitamin D in managing diabetic nephropathy by targeting AGT.