Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats

Wu-Wong, J. Ruth; Noonan, William T.; Nakane, Masaki; Brooks, Kristin A; Segreti, Jason A.; Polakowski, James S.; Cox, Bryan F.

doi:10.1155/2010/625852

Cited by 42 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, low-dose administration trended to de- crease SBP without statistical difference. To our knowledge, modulation of blood pressure by paricalcitol administration has not been shown (19,46,54). As expected, mice given aliskiren exhibited a significant decrease in SBP compared with nontreated diabetic mice.…”

Section: Discussionsupporting

confidence: 61%

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Riera

Anguiano

Clotet

et al. 2016

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

-Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 g/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H 2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies. diabetic nephropathy; renin-angiotensin system; angiotensin-converting enzyme 2; animal model DIABETIC NEPHROPATHY IS THE leading cause of end-stage renal disease in the developed world (34). Previous studies have suggested that the renin-angiotensin system (RAS) is a major mediator of progressive renal injury in diabetic nephropathy. Drugs that target the RAS, including angiotensin-converting enzyme inhibitors and ANG II type 1 receptor blockers, have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (1, 4, 6, 21, 31). The systemic components of the RAS are altered in diabetes mellitus (32) and the intrarenal RAS is thought to play the major damaging role (25). The angiotensin-converting enzyme 2 (ACE2) has been identified in humans and differs from angiotensin-converting enzyme (ACE) in that it preferentially removes carboxy-terminal hydrophobic or basic amino acids (5, 12). Whereas ACE forms ANG II from ANG I, ACE2 is a major route of ANG II metabolism to ANG 1-7 (5, 39). ...

show abstract

Section: Discussionsupporting

confidence: 61%

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Riera

Anguiano

Clotet

et al. 2016

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Despite these findings, supplementation with the active vitamin D analogue paricalcitol did result in amelioration of the aortic endothelial permeability and limited the gap formation observed in CKD rats. In line with our results, Wu‐Wong et al have reported that paricalcitol can improve endothelial‐dependent relaxation in uremic rats independent from effects on PTH serum concentration 16, 17. Recently, randomized clinical trials conducted in patients with CKD also demonstrated that treatment with active vitamin D leads to significantly favorable changes in endothelial function 18, 19, 33, 34, 35…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, while in vitro studies suggested a protective role for vitamin D in ameliorating damaged endothelium,12, 13 experimental in vivo CKD studies have primarily focused on the prevention of vascular calcification of the medial layer and heart failure9, 14, 15 but paid little attention to structural endothelial damage. A small number of prior studies have suggested benefits of the active vitamin D analogue paricalcitol on endothelial stability in animal models of CKD16, 17 and even in patients 18, 19. Interestingly, paricalcitol supplementation increased kidney and serum α‐Klotho levels in in vivo models of CKD 20, 21.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundDysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.Methods and ResultsIn a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.ConclusionsOur results demonstrate that paricalcitol attenuates the CKD‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.

show abstract

“…Vitamin D receptor activation by this compound ameliorates endothelium-dependent vasodilatation in subtotally nephrectomized rats, an effect which is completely independent of BP and parathormone levels. 23 As in previous studies applying the same technique, 24 patients with CKD enrolled in this study exhibited endothelial dysfunction. Paricalcitol elicited a coherent rise in the endothelium-dependent FMD response to ischemia in these patients with a 61% increase versus placebo.…”

Section: Discussionmentioning

confidence: 67%

Paricalcitol and Endothelial Function in Chronic Kidney Disease Trial

et al. 2014

View full text Add to dashboard Cite

Abstract-Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 μg/d×12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (−75 pg/mL; 95% confidence interval, -90 to -60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5-36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6±2.9%) and placebo (3.6±2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the betweengroup difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3-3.1%) was significant (P=0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitoltreated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment.

show abstract

Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats

Cited by 42 publications

References 34 publications

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Paricalcitol and Endothelial Function in Chronic Kidney Disease Trial

Contact Info

Product

Resources

About