Hepatocyte Nuclear Factors 4αand 1αRegulate Kidney Developmental Expression of Drug-Metabolizing Enzymes and Drug Transporters

Abstract

The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule (PT) is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors, which are thought to "sense" deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including hepatocyte nuclear factor 4a (Hnf4a) and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

“…HNF4␣ is mainly expressed in the liver, kidney, pancreas, and intestine (5,11,18,20,23,24,29,54). In the kidney, HNF4␣ is abundant in proximal tubules.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…For example, it is known that drug transporter expression occurs early in embryogenesis; indeed, several renal drug transporters are expressed transiently in the developing central nervous system and other tissues (94). Late in rodent gestation, the expression is largely limited to the future proximal tubules of the kidney (15,95); thereafter, there is a burst in renal expression around the time of birth, eventually reaching (and perhaps overshooting for a short time) adult expression (9,96). This is paralleled by functional changes, such as increasing PAH clearance (96).…”

“…Through a combination of systems-biology approaches involving analysis of transcriptomics and combining chromatin immunoprecipitation with DNA sequencing (ChIP-seq) data, it has been possible to implicate, and then show experimentally, that hepatocyte nuclear factor-4a and hepatocyte nuclear factor-1a are major regulators of OAT and OCT expression, as well as other proximal tubule transporters and drugmetabolizing enzymes (9,74,75). Unlike the extensive modern understanding of drug metabolism in the liver, the role of proximal tubule drug-metabolizing enzymes, in the context of both the proximal tubule cell and systemic physiology, is not well understood and is probably underappreciated.…”

“…Apart from excreting unmodified small molecule drugs, the kidney handles many conjugated metabolites, most of which are produced by phase 1 and phase 2 metabolism in the liver (e.g., products of hydroxylation, sulfation, and glucuronidation reactions) (8). Genes for phase 1 and 2 reactions are also expressed in the kidney and are likely to be very important in metabolic functions of the proximal tubule cells of kidney as well (9), although this area of research is underexplored.…”

The importance of drug transporters in human pluripotent stem cells and in early tissue differentiation

“…In induced and directed hepatocyte, enterocyte or blood-brain epithelial 600 cell differentiation from embryonic stem cells, in addition to ABC transporters (see above), several SLC-type transporters are important developmental indicators. [1,15,[53][54][55][56][57][58][59][60] During stem cell differentiation into early kidney tissues, the expression patterns of the SLC12A1 (NA/K/Cl -thick 605 ascending limb the of Henle's loop), A3 (Na/Cl -distal convoluted tubule) and the SLC34A1 (Na/phosphate, proximal tubule) transporter proteins can be efficiently used as markers for kidney tubule development. [61] Similarly, specific substrate transporters in the SLC1 (PM glutamate, 610 aspartate or other neurotransmitter carriers), in the SLC6 (PM neurotransmitter and amino acid transporters) and in the SLC17 family (vesicular glutamate transporters) are recognized as regulated marker proteins, especially in neuronal differentiation.…”