Abstract
There is evidence to suggest that abnormal angiogenesis, inflammation, and fibrosis drive diabetic nephropathy (DN). However, there is no specific treatment to counteract these processes. We aimed to determine whether DIAVIT, a natural Vaccinium myrtillus (blueberry) and Hippophae Rhamnoides (sea buckthorn) extract, is protective in a model of type II DN. Diabetic db/db mice were administered DIAVIT in their drinking water for 14 weeks. We assessed the functional, structural, and ultra-structural phenotype of three experimental groups (lean+vehicle, db/db+vehicle, db/db+DIAVIT). We also investigated the angiogenic and fibrotic pathways involved in the mechanism of action of DIAVIT. Diabetic db/db mice developed hyperglycaemia, albuminuria, and an increased glomerular water permeability; the latter two were prevented by DIAVIT. db/db mice developed fibrotic glomeruli, endothelial insult, and glomerular ultra-structural changes, which were not present in DIAVIT-treated mice. Vascular endothelial growth factor A (VEGF-A) splicing was altered in the db/db kidney cortex, increasing the pro-angiogenic VEGF-A165 relative to the anti-angiogenic VEGF-A165b. This was partially prevented with DIAVIT treatment. Delphinidin, an anthocyanin abundant in DIAVIT, increased the VEGF-A165b expression relative to total VEGF-A165 in cultured podocytes through phosphorylation of the splice factor SRSF6. DIAVIT, in particular delphinidin, alters VEGF-A splicing in type II DN, rescuing the DN phenotype. This study highlights the therapeutic potential of natural drugs in DN through the manipulation of gene splicing and expression.
Highlights
Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) in the USA and across the world, affecting 50% of diabetic patients [1,2,3]
DIAVIT treatment did prevent the progressive increase in albuminuria observed in db/db mice (Fig 1B; urinary albumin creatinine ratio (uACR) at 14 weeks: lean, 12.8 ± 1.2 μg/mg; db/db, 312.3 ± 154.4 μg/mg; db/db + DIAVIT, 138.7 ± 19.4 μg/mg; values normalized to baseline shown in S2 Fig)
We clearly show that delphinidin promotes VEGF-A165b expression relative to VEGF-A165; delphinidin has an inhibitory effect on vascular endothelial growth factor A (VEGF-A) total expression, which is not observed in response to the DIAVIT extract
Summary
Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) in the USA and across the world, affecting 50% of diabetic patients [1,2,3]. DIAVIT extract to treat diabetic nephropathy current treatments of choice [4], but many DN patients still progress to ESRD. In DN, alterations of the glomerular filtration barrier (GFB) result in increased permeability to protein; such changes include glomerular basement membrane (GBM) thickening, mesangial matrix expansion (MME), podocyte detachment, and glomerular endothelial cell damage [5,6]. Activation of the transcription factor p65 nuclear factor kappa B (p65-NFĸB) is linked to the regulatory pathways that underlie the pro-inflammatory and pro-fibrotic response [13], and an increase in p65-NFĸB translocation to the nucleus has been shown in human DN [14]
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