Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease

Abstract

Purpose of review: In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD.

Recent findings: In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes.

Summary: ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome.

FIGURE 1

Alkaline phosphatase is ubiquitously expressed; however, the contribution of alkaline phosphatase from different tissues to the circulating alkaline phosphatase activity may vary. Under healthy conditions, liver and bone isoforms of tissue-nonspecific isozyme alkaline phosphatase comprise approximately 50% each of the total circulating alkaline phosphatase activity. Intestine alkaline phosphatase can comprise up to 10% of the circulating alkaline phosphatase activity in individuals with blood group B or 0, but less than 3% in individuals with blood group A. Circulating alkaline phosphatase predicts disease-related outcomes, for example cardiovascular disease or mortality, but to which extend alkaline phosphatase derived from specific tissues contributes to the total circulating alkaline phosphatase activity in pathologic conditions remains largely undetermined. Designed by Macrovector and Brgfx - Freepik.com.

Box 1

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FIGURE 2

Summary of mechanisms linking dephosphorylation by alkaline phosphatase to normal and pathophysiological processes. LPS, lipopolysaccharides; MMP, metalloproteinase; OPN, osteopontin; Pi, phosphate; PL, pyridoxal; PLP, pyridoxalphosphate; PPi, pyrophosphate.

FIGURE 3

Chromatin is comprised of DNA and proteins that generate a compact structure critical for packaging and stability of eukaryotic chromosomes. The primary protein components are histones, around which the DNA is wound to form a nucleosome. Epigenetics involves covalent modifications to chromatin that does not affect the underlying DNA sequence. Covalent modifications to chromatin impact both chromatin structure and recruitment of transcription complexes that, in effect, switch genes on or off. These dynamic epigenetic modifications are carried out by adding (writing) and removing (erasing) posttranslational modifications, followed by ‘reading’, which dictates gene expression and eventual phenotypic response.

FIGURE 4

Chromatin acetylation is an epigenetic modification associated with open chromatin structure and active transcription. Bromodomain and extraterminal proteins are ‘chromatin readers’ that bind acetylated lysine on histones or transcription factors via two tandem bromodomains 1 and 2 and recruit transcriptional machinery (e.g. positive transcription elongation factor and RNA polymerase II) to drive expression of bromodomain and extraterminal sensitive genes. Apabetalone is an orally available small molecule inhibitor of bromodomain and extraterminal bromodomains that causes bromodomain and extraterminal protein release from chromatin and, as a consequence, downregulation of bromodomain and extraterminal sensitive gene transcription. Apabetalone preferentially targets bromodomain 2 (represented by yellow halo), a characteristic that differentiates it from pan-bromodomain and extraterminal inhibitors that bind bromodomains 1 and 2 with equal affinity.