Abstract
Renal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in pathological conditions. In diabetic nephropathy (DN), podocytes become structurally and functionally compromised. Nephrin, a structural backbone protein of the slit diaphragm, acts as regulator of podocyte intracellular signalling with renoprotective role. Vitamin D3 through its receptor, VDR, provides renal protection in DN but limited data exist about its effect on podocytes. In this study, we used isolated rat glomeruli to assess podocalyxin and nephrin expression after treatment with the 1,25‐dihydroxyvitamin D3 analogue paricalcitol in the presence of normal and diabetic glucose levels. The role of 1,25‐dihydroxyvitamin D3 (calcitriol) and its analogue, paricalcitol, on podocyte morphology and survival was also investigated in the streptozotocin (STZ)‐diabetic animal model. In our ex vivo model, glomeruli exhibited high glucose‐mediated down‐regulation of podocalyxin, and nephrin, while paricalcitol reversed the high glucose‐induced decrease of nephrin and podocalyxin expression. Paricalcitol treatment enhanced VDR expression and promoted VDR and RXR co‐localization in the nucleus. Our data also indicated that hyperglycaemia impaired survival of cultured glomeruli and suggested that the implemented nephrin down‐regulation was reversed by paricalcitol treatment, initiating Akt signal transduction which may be involved in glomerular survival. Our findings were further verified in vivo, as in the STZ‐diabetic animal model, calcitriol and paricalcitol treatment resulted in significant amelioration of hyperglycaemia and restoration of nephrin signalling, suggesting that calcitriol and paricalcitol may provide molecular bases for protection against loss of the permselective renal barrier in DN.
Highlights
Active vitamin D3 is an important hormone implicated in prevention and treatment of hyperparathyroidism in dialysis patients
Glomeruli cultured in the presence of 5 mM glucose displayed enhanced nephrin and PODXL expression levels when they were exposed to VDR activator (VDRA) (Fig. 1A)
We observed that in glomeruli exposed to 25 mM glucose, VDRA increased the expression levels of nephrin and PODXL which were apparently restored to normal levels (Fig. 1B)
Summary
Active vitamin D3 is an important hormone implicated in prevention and treatment of hyperparathyroidism in dialysis patients. Increasing amount of data suggests a beneficial role of vitamin D3 in chronic kidney disease (CKD), associated with increased survival of patients [1, 2]. One of the most common causes of end-stage renal disease is DN [3]. Vitamin D may provide renoprotection in DN in part via the renin-angiotensin system [4,5,6]. DN is characterized by pathological changes, such as thickening of the glomerular basement membrane and mesangial expansion and by the clinical hallmark of proteinuria [7]. The field of research on DN has mainly focused on podocytes which are important for maintaining glomerular permselectivity [8]
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