Vitamin D upregulates endothelin-1, ETBR, eNOS mRNA expression and attenuates vascular remodelling and ischemia in kidney fibrosis model in mice.

Abstract

We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression.

• Authors: N Arfian, M Hh Kusuma, N Anggorowati, D B Nugroho, A Jeffilano, Y Suzuki, K Ikeda, N Emoto
• Journal: Physiological research (Physiol Res) Vol. 67 Issue Suppl 1 Pg. S137-S147 (06 27 2018) ISSN: 1802-9973 [Electronic] Czech Republic
• PMID: 29947534 (Publication Type: Journal Article)

Chemical References

• Endothelin-1
• RNA, Messenger
• Receptor, Endothelin B
• Vitamin D
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse

Topics

• Animals
• Endothelin-1 (biosynthesis)
• Fibrosis
• Human Umbilical Vein Endothelial Cells
• Humans
• Ischemia (drug therapy, metabolism)
• Kidney Diseases (drug therapy, metabolism)
• Male
• Mice
• Nitric Oxide Synthase Type III (biosynthesis)
• RNA, Messenger (biosynthesis)
• Receptor, Endothelin B (biosynthesis)
• Up-Regulation (drug effects, physiology)
• Vascular Remodeling (drug effects, physiology)
• Vitamin D (pharmacology, therapeutic use)