Calcitriol Supplementation Improves Endothelium-Dependent Vasodilation in Rat Hypertensive Renal Injury

Abstract

Background/Aims: Vitamin D increases renal expression of klotho in normotensive rats. Klotho reduces oxidative stress. Methods: In this study, we aimed to determine if vitamin D would suppress oxidative stress using 4 groups of hypertensive rats: uninephrectomized, stroke-prone, spontaneously hypertensive rats fed a high-salt (6%) diet (controls; C); those treated with irbesartan (I); those treated with calcitriol (V); and those treated with both irbesartan and calcitriol (I+V). Results: Systolic blood pressure was higher in the C group than in the I and I+V groups. Albuminuria was attenuated in groups I, V, and I+V. Renal angiotensin II (AngII) concentration was lower in groups I and I+V than in group C, and plasma AngII levels of groups I and V were higher and lower than those in group C, respectively. Compared with group C, renal klotho expression, 8-epi-prostaglandin F2α excretion, and acetylcholine-induced decrease in blood pressure improved in the V and I+V groups. Conclusions: The data indicate that irbesartan effectively decreases blood pressure and renal AngII levels, and improves albuminuria. Our findings indicate that vitamin D enhances klotho expression, suppressing oxidative stress and albuminuria without substantial changes in renal AngII levels. These results suggest that the amelioration of endothelium function by vitamin D involves free klotho.

Antialbuminuric actions of calcilytics in the remnant kidney

“…Calcitriol and ronacaleret were administered by an osmotic pump that was implanted subcutaneously (Alzet, Cupertino, CA) and by daily subcutaneous injection, respectively. Calcitriol was dissolved in ethanol and used at a dose previously reported not to cause hyperphosphatemia (35). From the first series of experiments, we selected the smallest dose of ronacaleret that was able to enhance klotho expression.…”

“…As previously described (11,22,35), total RNA from the aorta or kidney cortex was extracted from ϳ50 mg of the tissue using a commercial kit (Isogen, Wako Pure Chemical, Osaka, Japan) according to the manufacturer's instructions. One microgram of total RNA was subjected to first-strand cDNA synthesis in a 20-l reaction mixture using a commercial kit (iScript cDNA Synthesis kit, Bio-Rad Laboratories, Tokyo, Japan).…”

“…Klotho induces phosphaturia directly by inhibiting proximal tubular reabsorption when presented on the luminal side (12), reducing serum phosphate. Klotho is detected in urine, which could be derived from paracellular transport at proximal tubules, filtration at glomeruli, and direct secretion into the luminal side by distal nephrons (35).…”

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

“…Urine and serum klotho levels were measured with ELISA. (4,8) In a third series of investigations, animal preparation was done similarly to the first series, excluding the placement of a renal interstitial catheter. A large dose of rh-klotho (100 mg/kg) or vehicle was administered as bolus injection directly into the aorta through the femoral artery (n ¼ 4 for each group).…”

“…Parathyroid hormone (PTH) induces 25-hydroxyvitamin D 3 1a-hydroxylase (1-OH) to generate 1,25VD. (7) Klotho binds to various proteins, including TRPCs, WNT, and receptors for VEGF, FGF, TGF-b, and IGF, (8)(9)(10)(11)(12)(13)(14) to elicit a wide variety of biological responses, including inhibition of fibrosis, epithelial-mesenchymal transition and cancer metastasis, and modulation of endothelial function and insulin action, as well as calcium-phosphate metabolism.…”