Paricalcitol attenuates cyclosporine-induced kidney injury in rats

Abstract

Despite its benefits, the clinical use of cyclosporine A (CsA) is limited by its nephrotoxic properties. Because paricalcitol (19-nor-1,25-hydroxyvitamin D(2)) has renoprotective effects, we tested whether it can blunt renal dysfunction and fibrosis in a rat model of CsA-induced nephropathy. Treatment with CsA decreased creatinine clearance, increased monocyte/macrophage infiltration, and increased the expression of inflammatory cytokines within the kidney. Paricalcitol reduced the decline in kidney function and pro-fibrotic changes and also blunted the increased transforming growth factor (TGF)-beta1 expression and Smad signaling. Using an in vitro model, we treated HK-2 cells with CsA and found that paricalcitol attenuated the CsA-induced increases in phosphorylated extracellular signal-regulated and c-Jun N-terminal kinases, and also prevented the activation of nuclear factor-kappaB. Paricalcitol effectively prevented TGF-beta1-induced epithelial-to-mesenchymal transitions and extracellular matrix accumulation as evidenced by attenuated collagen deposition and fibrosis in CsA-treated rats. In addition, paricalcitol decreased the number of TUNEL-positive nuclei and reduced the expression of pro-apoptotic markers in CsA-treated HK-2 cells. Thus, paricalcitol appears to attenuate CsA-induced nephropathy by suppression of inflammatory, pro-fibrotic, and apoptotic factors through inhibition of the nuclear factor-kappaB, Smad, and mitogen-activated protein kinase signaling pathways.

Antioxidant and renoprotective effects of paricalcitol on experimental contrast-induced nephropathy model

“…Of note, paricalcitol has been shown to improve cardiac oxidative injury in uremic and aortic oxidative injury in atherosclerotic rats [9,23]. Paricalcitol has been shown to attenuate ciclosporin Ainduced nephropathy by suppression of inflammatory and apoptotic factors through inhibition of some protein kinase-signalling pathways [5]. De Zeeuw et al [24] demonstrated that paricalcitol lowers albuminuria in patients with diabetic nephropathy.…”

“…In addition to its primary role in calcium metabolism and bone mineralisation, vitamin D and its non-hypercalcemic analogue paricalcitol have pleiotropic and antioxidant effects on cellular homeostasis [5]. Studies in experimental nephropathy models have focused on the effects of vitamin D and paricalcitol on glomerular damage and tubular toxicity [6][7][8].…”

Association of Vitamin D deficiency, cellular hypoxia, and caspase-3 with renal disease in pediatric diabetic nephropathy

“…Beyond its role in calcium and phosphate homeostasis, vitamin D is an important modulator of cellular proliferation, inflammation, differentiation, and immunity [11]. Vitamin D3 attenuates kidney injury by suppressing fibrosis, inflammation, and apoptosis, by inhibiting multiple pathways known to play a role in kidney injury, including the renin-angiotensinaldosterone system (RAAS), the nuclear factor-κB (NF-κB) [11,12], the transforming growth factor-β (TGF-β)/Smad [12][13][14][15].…”

Beyond Proteinuria: Apoptosis and Vitamin D3 State in Children with Diabetic Nephropathy

“…Beyond its role in calcium and phosphate homeostasis, vitamin D is an important modulator of cellular proliferation, inflammation, differentiation, and immunity [14]. Vitamin D3 attenuates kidney injury by suppressing fibrosis, inflammation, and apoptosis, by inhibiting multiple pathways known to play a role in kidney injury, including the renin-angiotensinaldosterone system (RAAS), the nuclear factor-κB (NF-κB) [15], the transforming growth factor-β (TGF-β)/Smad [16].…”