Chronic Kidney Disease Alters Vitamin A Homeostasis via Effects on Hepatic RBP4 Protein Expression and Metabolic Enzymes

Abstract

Vitamin A, via retinoic acid (RA), is a critical micronutrient. Normally, plasma concentrations are tightly regulated. Concentrations of vitamin A metabolites (13cis‐RA, atRA) and relationships between RBP4 and retinoids have never been fully evaluated in adult patients with CKD. We measured retinoid and RBP4 concentrations in plasma and urine from 55 adult patients with CKD and 21 matched healthy subjects. RBP4 and retinol levels were increased approximately twofold in patients with CKD, with a negative correlation between plasma retinol and eGFR (p = 0.006) and plasma RBP4 and eGFR (p = 0.0007). RBP4 renal clearance was higher in patients with CKD than healthy subjects but not associated with eGFR. Circulating concentrations of atRA increased and concentrations of 13cis‐RA decreased in subjects with CKD with no change in RA‐to‐retinol ratio. Increases in circulating retinol, RBP4, and atRA may be due to increased hepatic RBP4 synthesis, retinyl ester hydrolysis, and/or hepatic secretion of RBP4‐retinol.

Amelioration of Diabetic Nephropathy Using a Retinoic Acid Receptorβ2 Agonist

“…These findings are consistent with multiple lines of evidence of aberrant renal retinoid homeostasis in DN (Raila et al, 2007;Frey et al, 2008;Starkey et al, 2010;Jing et al, 2016), and our previous research (Trasino et al, 2015) where we demonstrated that even with sufficient dietary VA and elevated serum ROL, renal and numerous tissue have marked reductions in retinoid levels and retinoid signaling (Trasino et al, 2015), suggesting that obesity and its related disorders such as DN, may lead to a state of tissue retinoid resistance (Trasino et al, 2015). It is noteworthy to highlight that renal retinoid resistance has been previously documented by our laboratory and others in human renal cancer (RC) (Guo et al, 2001), which show a distinct resistance to the therapeutic effects of retinoids due to loss of RARβ2 expression (reviewed in (Tang and Gudas, 2011), and that reestablishing RARβ2 expression in RC (Touma et al, 2005) restores sensitivity to the anti-tumor effects of retinoids (Touma et al, 2005;Tang and Gudas, 2011).…”

“…Whether RARβ2 is involved in the altered retinoid metabolism in DN and CKD remains unclear, as is the mechanism by which renal ROL, retinoid homeostasis and RAR signaling are altered in obesity and DN (Raila et al, 2007;Frey et al, 2008;Starkey et al, 2010;Jing et al, 2016). Nevertheless, if as in RC, RARβ is necessary for cellular RA responsiveness in DN and CKD, our data demonstrating significantly higher renal mRNA levels of RARβ2, RARγ, CRBP1 in HFD+AC261 treated mice compared to HFD-fed mice is noteworthy and collectively suggest that AC261 treatment engages retinoid pathways and prevents or reverses the reductions of renal retinoid signaling in HFD-fed mice.…”

“…Perturbations in renal VA metabolism and RA signaling appear to be involved in the onset of DN, as reductions in renal VA metabolism and RA signaling occur in mouse and human T2D-DN (Raila et al, 2007;Frey et al, 2008;Starkey et al, 2010;Trasino et al, 2015;Jing et al, 2016) and albuminuria promotes progression of renal This article has not been copyedited and formatted. The final version may differ from this version.…”

“…Pharmacological approaches that increase podocyte responsiveness to RA signaling mitigate progression of experimental renal injury (Sagrinati et al, 2006;Lasagni et al, 2015). However, given the aberrant renal metabolism of VA and RA in T2D and DN (Trasino et al, 2015), a novel approach for development of retinoidmediated DN therapies is the use of synthetic agonists for RARs, as they not as likely to be affected by altered VA metabolism that occurs in T2D-DN (Starkey et al, 2010;Trasino et al, 2015;Jing et al, 2016). RARβ is expressed predominantly in glomerular cells in the adult kidney (Manzano et al, 2000;Zhong et al, 2011;Uhlén et al, 2015), and RARβ2 is the most relevant RARβ isotype in renal development (Batourina et al, 2001).…”

Plasma Level of Retinol-Binding Protein 4, N-Terminal proBNP and Renal Function in Older Patients Hospitalized for Heart Failure

“…It has been shown that fenretinide (a synthetic retinoid that disrupts binding of RBP4 to TTR) enhances renal excretion and leads to decreased RBP4 concentration levels in mice [31]. Jing et al [32] suggested that altered hepatic synthesis and secretion of RBP4 and retinol or disturbed retinoid homeostasis were caused by uremic toxins.…”