Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme

Abstract

Patients with chronic kidney disease (CKD) suffer from arterial media calcification and a disturbed bone metabolism. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the calcification inhibitor pyrophosphate (PPi) into inorganic phosphate (Pi) and thereby stimulates arterial media calcification as well as physiological bone mineralization. This study investigates whether the TNAP inhibitor SBI-425, PPi or the combination of both inhibit arterial media calcification in an 0.75% adenine rat model of CKD. Treatments started with the induction of CKD, including (i) rats with normal renal function (control diet) treated with vehicle and CKD rats treated with either (ii) vehicle, (iii) 10 mg/kg/day SBI-425, (iv) 120 µmol/kg/day PPi and (v) 120 µmol/kg/day PPi and 10 mg/kg/day SBI-425. All CKD groups developed a stable chronic renal failure reflected by hyperphosphatemia, hypocalcemia and high serum creatinine levels. CKD induced arterial media calcification and bone metabolic defects. All treatments, except for SBI-425 alone, blocked CKD-related arterial media calcification. More important, SBI-425 alone and in combination with PPi increased osteoid area pointing to a less efficient bone mineralization. Clearly, potential side effects on bone mineralization will need to be assessed in any clinical trial aimed at modifying the Pi/PPi ratio in CKD patients who already suffer from a compromised bone status.

The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization

“…TNAP inhibitors blocked norepinephrine dependent renovascular and blood pressure responses indicating the importance of TNAP in the kidney. The detrimental role of TNAP is seen in chronic kidney disease (CKD) where its activation leads to arterial media calcification resulting in stiffening of the blood vessels [ 167 , 168 ]. In CKD, calcification inhibitors such as MGP and PP i are decreased which results in ectopic mineralization of the artery wall [ 169 ].…”

“…Single dose of SBI-425 at 10mg/kg/day administered orally or through an intravenous route produced promising results in the TNAP over expressing mice. SBI-425 at 10 or 30mg/kg/day also exerted a positive role in preventing VC in mice models, impairing PP i generation and preventing aorta calcification in CKD mice fed with phosphorous and an adenine rich diet [ 168 ]. Oral administration of SBI-425 decreased accumulation of coronary calcium and LV hypertrophy in wicked high cholesterol mouse models [ 178 ].…”

The Contribution of Extracellular Vesicles From Senescent Endothelial and Vascular Smooth Muscle Cells to Vascular Calcification

“…Medial arterial calcification consists of hydroxyapatite crystals, which are calcium and phosphate mineral deposits found in bones (8)(9)(10)(11). This type of calcification is a characteristic of CKD patients with CVD (6,(12)(13)(14)(15). The pathology of medial arterial calcification is multifactorial (12).…”

“…This type of calcification is a characteristic of CKD patients with CVD (6,(12)(13)(14)(15). The pathology of medial arterial calcification is multifactorial (12). It is a gradual process resulting from disruptions in calcium, phosphate, and vitamin D homeostasis (8,16).…”

“…Chronic inflammatory diseases, including CKD, are considered synergistic pathologies due to the high risk of comorbidities, including CVD (12,(22)(23)(24). Furthermore, aging precipitates the appearance of age-related pathologies such as CKD and/or CVD, and vice versa; thus, these chronic inflammatory diseases trigger premature aging (19,23).…”