Effect of resveratrol on progression of polycystic kidney disease: a case of cautious optimism.

Abstract

NDT Advance Access published May 17, 2016 Nephrol Dial Transplant (2016) 0: 1–4 doi: 10.1093/ndt/gfw097 In Focus Effect of resveratrol on progression of polycystic kidney disease: a case of cautious optimism Division of Nephrology and Hypertension, University of California, Irvine, 333 City Blvd West, Orange, CA 92868, USA and 2 Long Beach VA Healthcare System, Nephrology Section, Long Beach, CA, USA Correspondence and offprint requests to: Hamid Moradi; E-mail: hmoradi@uci.edu Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited genetic cause of chronic kidney disease, af- fecting 1 in 500 individuals in the USA. In addition, ADPKD is the most common genetic cause of end-stage renal disease (ESRD), accounting for ∼7–10% of patients on renal replace- ment therapy [1]. It is characterized by the development of fluid-filled cysts in the renal tubules and their progressive en- largement over time leading to the distortion of renal tissue and ongoing kidney damage and culminating in ESRD [2, 3]. At the molecular level, ADPKD is caused by mutations in the PKD1 (85%) or PKD2 (15%) genes, which encode the cilia-associated polycystin-1 (PC1) and polycystin-2 (PC2) pro- teins [4]. PC1 and PC2 are membrane proteins that are located in the primary cilia of the tubular epithelial cells, and while the ligand for PC1 has not been identified, PC2 is most likely a non- selective calcium channel [2, 3]. There are multiple mechan- isms by which mutations in the PKD1 and PKD2 genes result in cystogenesis, including increased cell proliferation, enhanced fluid secretion, abnormal cell–matrix interaction, alterations in cell polarity and abnormal ciliary structure and function [2]. However, there are also several nongenetic pathways that can contribute to the progression and modify the severity of ADPKD. This is evidenced by the fact that patients with ADPKD have large intrafamilial variability in renal function even between monozygotic twins and siblings [5]. In addition, in monozygotic twins, there can be significant differences in the age at which ESRD is reached, thereby highlighting the role of nonhereditary pathways in ADPKD-associated renal injury and progression of disease [5]. These include pathways related to growth factor and cytokine signaling [6]. The importance of in- flammation and cytokine signaling in PKD has been established in numerous studies over the past few decades. Gardner et al. [7] noted high concentrations of inflammatory chemokines and © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. cytokines in the cyst fluid from patients with ADPKD. Cowley et al. [8] subsequently demonstrated that increased expression of monocyte chemoattractant protein-1 (MCP-1) was accom- panied by accumulation of macrophages in the kidneys of rats with ADPKD. It is now known that MCP-1 is present in the urine of patients with ADPKD and that high levels of urinary MCP-1 correlate with the rate of cyst growth and progression of disease [9, 10]. In line with these discoveries, large numbers of activated macrophages have been found around renal cysts in animal models of ADPKD whose depletion inhibited epithelial cell proliferation and cyst growth and improved renal function [11]. Furthermore, Swenson-Fields et al. [12] demonstrated that increased numbers of macrophages expressing the M2 marker CD163 are also present in the interstitium of kidneys of patients with both AD and autosomal recessive PKD, some of which are in close proximity to the cysts. In turn, the cyst epithelial cells stimulated macrophage differentiation toward a distinct M2-like phenotype that, based on in vitro studies, pro- moted proliferation and microcyst formation. Furthermore, re- cent studies have demonstrated that macrophage migration inhibitory factor (MIF) is upregulated in the epithelial cells lining renal cysts and that this protein accumulates in the cyst fluid of patients with ADPKD [13]. MIF was found to be a key regulator of cyst growth in ADPKD via several converging mechanisms, including cytokine signaling. It was shown that MIF-dependent macrophage recruitment was associated with increased MCP-1 and tumor necrosis factor α (TNF-α) production, which in turn increased expression of MIF. Hence, a positive feedback loop between inflammation, inflam- matory cytokines and MIF was identified, with the end result being progression of the disease [13]. Therefore, besides the gen- etic abnormalities that instigate the underlying disease in ADPKD, inflammation, macrophage activation, differentiation Downloaded from http://ndt.oxfordjournals.org/ at University of California, Irvine on May 18, 2016 Hamid Moradi 1,2 and Nosratola D. Vaziri 2