101 It is known that heavy proteinuria develops with pathological changes of mesangial apoptosis and recruitment of neutrophils and monocytes into the mesangium, followed by release of chemoattractant, pro-inflammatory cytokines and subsequent mesangial hyperproliferation and matrix expansion. Blocking this process is associated with significant reductions in urinary protein

excretion. Panichi’s group were able to ameliorate mesangial inflammation with the administration of 1,25-OHD, which reduced inflammatory EGFR activation cell recruitment and cytokine production (measured as urinary IL-6), together with associated decreases in mesangial cell proliferation.104 Similar results were obtained by Makibayashi’s lab using the same model but with the VDR activating 1,25-OHD analogue 22-oxa-calcitriol (OCT).105 In addition to the cellular changes reproduced, this group also demonstrated a reduction in mesangial matrix, Selumetinib solubility dmso with diminished expression of mRNA and staining for type I and IV collagen, and α-smooth muscle actin (α-SMA). This effect may be mediated through modulation of transforming growth factor-β (TGF-β) which is known to modulate mesangial cell proliferation106 and in Makibayashi’s study diseased glomeruli showed strong staining for TGF-β1 with upregulated mRNA expression which was greatly reduced Metalloexopeptidase in the treatment

group.105 This effect on TGF-β had been seen in an earlier study by Schwarz et al. who used subtotally nephrectomized rats as a model of glomerular remodelling and sclerosis.107 In 1,25-OHD-treated diseased rats, the group effectively reduced glomerulosclerosis and mean volume of individual glomeruli – a marker of hypercellularity, matrix expansion and proliferation. This was associated with diminished in situ hybridization for cellular TGF-β, and most importantly a significant reduction in albuminuria.107 The clinical translation of this work has recently been published by the VITAL investigators.108 In this well-designed placebo-controlled, double-blind trial,

281 patients with diabetic nephropathy were randomized to placebo, 1 µg/day or 2 µg/day paricalcitol, in addition to standard renin-angiotensin blockade for 6 months. There was a significant reduction in urinary albumin excretion in the paricalcitol groups compared with placebo which demonstrated a dose–response relationship and was most evident between the placebo and 2 µg/day groups (−3% (95% CI: −16 to 13) vs−20% (95% CI: −30 to −8), P = 0.053). This was accompanied by a substantial, early sustained reduction in eGFR (−3 to −5 mL/min/1.73 m2, P = 0.055) and systolic blood pressure (−3 to −9 mmHg, P = 0.033), implying that paricalcitol may improve albuminuria via suppression of the renin-angiotensin system.