Role of Vitamin D in Maintaining Renal Epithelial Barrier Function in Uremic Conditions

Abstract

As current kidney replacement therapies are not efficient enough for end-stage renal disease (ESRD) treatment, a bioartificial kidney (BAK) device, based on conditionally immortalized human proximal tubule epithelial cells (ciPTEC), could represent an attractive solution. The active transport activity of such a system was recently demonstrated. In addition, endocrine functions of the cells, such as vitamin D activation, are relevant. The organic anion transporter 1 (OAT-1) overexpressing ciPTEC line presented 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1) and vitamin D receptor (VDR), responsible for vitamin D activation, degradation and function, respectively. The ability to produce and secrete 1α,25-dihydroxy-vitamin D3, was shown after incubation with the precursor, 25-hydroxy-vitamin D3. The beneficial effect of vitamin D on cell function and behavior in uremic conditions was studied in the presence of an anionic uremic toxins mixture. Vitamin D could restore cell viability, and inflammatory and oxidative status, as shown by cell metabolic activity, interleukin-6 (IL-6) levels and reactive oxygen species (ROS) production, respectively. Finally, vitamin D restored transepithelial barrier function, as evidenced by decreased inulin-FITC leakage in biofunctionalized hollow fiber membranes (HFM) carrying ciPTEC-OAT1. In conclusion, the protective effects of vitamin D in uremic conditions and proven ciPTEC-OAT1 endocrine function encourage the use of these cells for BAK application.

Advances in predictive in vitro models of drug-induced nephrotoxicity

“…Flow through the basolateral compartment is also possible. Exposure of these hollow fibres to uraemic toxins increased IL-6 expression and induced leakage of FITC-labelled inulin, indicating disruption of the epithelial tight junctions 145 . Notably, the convex arrangement of tubular epithelial cells on the exterior of the hollow fibre is not reflective of their arrangement in vivo — a caveat that should be addressed in future designs.…”

A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection

“…Calcitriol regulates antimicrobial proteins (cathelicidin and β-defensin), responsible for modifying intestinal microbiota to a healthier composition and supporting the gut barrier [10,14], as well as protecting the lungs against infection [15]; increases tight junction protein expression, E-cadherin, and connexion 43 in the gut [16][17][18]; maintains renal epithelial barrier function [19]; enhances corneal epithelial barrier function [20] Vitamin C…”

“…It also stimulates tight junction protein expression, E-cadherin, and connexin 43 in the gastrointestinal tract, which function as structural precursors of gap junctions and provide a communication pathway between the cytosol and extracellular environment of the intestinal barrier [16][17][18]. They also maintain renal epithelial barrier function [19], and enhance corneal epithelial barrier function [20]. The gastrointestinal tract is an important line of defense in which epithelial cells provide a physical and biochemical barrier and work in concert with immune cells and the gut microflora (some of which produce an array of compounds such as bacteriocins) to strengthen the gut barrier, fight off pathogens, and limit their direct contact with the epithelium [81].…”

Bioengineering Organs for Blood Detoxification

“…[62a,76a] The ciPTEC were also shown to secrete an active form of vitamin D when exposed to a mix of uremic toxins at concentrations that match those found in CKD patients. [79] Considering the progressive reduction of active vitamin D in these patients, this feature could be an exquisite addition to the function of the BAK system. Moreover, it has been reported that conventional hemodialysis removes vitamin D, [80] thus ciPTEC could become an important source of this metabolite.…”