Effects of calcitriol and paricalcitol on renal fibrosis in CKD

Abstract

Background In chronic kidney Disease (CKD) the activation of the renin-angiotensin-aldosterone system and renal inflammation stimulate renal fibrosis and the progression to end-stage renal disease. The low levels of vitamin D receptor (VDR) and its activators (VDRAs) contribute to worsen secondary hyperparathyroidism and renal fibrosis. Methods The 7/8 nephrectomy model of experimental chronic renal failure (CRF) was used to examine the antifibrotic effects of treatment with two VDRAs (paricalcitol and calcitriol at equivalent doses (3/1 dose ratio) during 4 weeks. Results CRF increased the activation of the renin-angiotensin-aldosterone system, renal inflammation and interstitial fibrosis. Paricalcitol treatment reduced renal collagen I and renal interstitial fibrosis by decreasing the activation of the renin-angiotensin-aldosterone system through renal changes in renin, ATR1 and ATR2 mRNAs levels and renal inflammation by decreasing renal inflammatory leukocytes (CD45), ADAM17 mRNA, TGF-β mRNA and protein and maintaining E-cadherin mRNA levels. Calcitriol showed similar trends without significant changes in most of these biomarkers. Conclusions Paricalcitol effectively attenuated the renal interstitial fibrosis induced by CRF through a combination of inhibitory actions on the renin-angiotensin-aldosterone system, inflammation and epithelial/mesenchymal transition.

Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease

“…These findings are consistent with human observational studies and uraemic rat models which show that VDRAs reduce proteinuria, and this may be through inhibition of podocyte injury and preservation of slit diaphragm proteins [44][45][46], in addition to its anti-inflammatory effects [13,14]. Similarly, the combination of paricalcitol and enalapril therapy in 5/6 nephrectomy rats resulted in a marked reduction in inflammation and fibrosis through suppression of RAAS and TGF-β gene expression [13]. This anti-inflammatory and anti-fibrotic action is unique to paricalcitol compared with calcitriol, thought to be due to differential gene expression [13,47,48].…”

“…This effect was independent of blood pressure and kidney size as there was no change to either with paricalcitol therapy alone. These findings are consistent with human observational studies and uraemic rat models which show that VDRAs reduce proteinuria, and this may be through inhibition of podocyte injury and preservation of slit diaphragm proteins [44][45][46], in addition to its anti-inflammatory effects [13,14]. Similarly, the combination of paricalcitol and enalapril therapy in 5/6 nephrectomy rats resulted in a marked reduction in inflammation and fibrosis through suppression of RAAS and TGF-β gene expression [13].…”

“…Similarly, the combination of paricalcitol and enalapril therapy in 5/6 nephrectomy rats resulted in a marked reduction in inflammation and fibrosis through suppression of RAAS and TGF-β gene expression [13]. This anti-inflammatory and anti-fibrotic action is unique to paricalcitol compared with calcitriol, thought to be due to differential gene expression [13,47,48]. In the present study, histological disease in the LPK rats at week 20 showed advanced cystic kidney disease, and there were no differences between the treatment groups.…”

“…The vitamin D group of fat-soluble secosteroids (D 1 -D 5 ), are widely utilised in chronic kidney disease (CKD) for the management of secondary hyperparathyroidism. Aside from their classical function in maintaining calcium homeostasis, the vitamin D secosteroids are also intranuclear regulators of cellular growth and differentiation [1,[8][9][10] and in vivo have been found to have additional renal-and vascular-protective properties, including the suppression of inflammation, fibrosis [11][12][13][14][15][16], and blood pressure [1,8,13]. In this regard, vitamin D receptor knockout mice develop severe hypertension [17] and, conversely, vitamin D receptor agonists (VDRAs) such as paricalcitol lower blood pressure in conjunction with inhibitors of the renin-angiotensin-aldosterone system (RAAS) in experimental CKD [18].…”

Signaling Pathways Involved in Diabetic Renal Fibrosis

“…In comparison, Chung et al (2017) figured out that PC might also alleviate renal fibrosis through the MAPK signaling pathway. In addition, PC shows a synergistic effect on the blocking of RAAS by ACEI ( Martínez-Arias et al, 2021 ), which possibly participates in the mitigation of EMT and renal fibrosis. A randomized clinical trial (PALIFE NCT01820078) has been designed to explore the effect of Paricalcitol on fibrosis on chronic renal diseases, but the trial has been terminated.…”