Vitamin A and retinoid signaling in the kidneys

Abstract

Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also play key roles in the function and repair of the kidney in adults. Kidneys filter 180-200 liters of blood per day and each kidney contains approximately 1 million nephrons, which are often referred to as the 'functional units' of the kidney. Each nephron consists of a glomerulus and a series of tubules (proximal tubule, loop of Henle, distal tubule, and collecting duct) surrounded by a network of capillaries. VA is stored in the liver and converted to active metabolites, most notably retinoic acid (RA), which acts as an agonist for the retinoic acid receptors ((RARs α, β, and γ) to regulate gene transcription. In this review we discuss some of the actions of retinoids in the kidney after injury. For example, in an ischemia-reperfusion model in mice, injury-associated loss of proximal tubule (PT) differentiation markers occurs, followed by re-expression of these differentiation markers during PT repair. Notably, healthy proximal tubules express ALDH1a2, the enzyme that metabolizes retinaldehyde to RA, but transiently lose ALDH1a2 expression after injury, while nearby myofibroblasts transiently acquire RA-producing capabilities after injury. These results indicate that RA is important for renal tubular injury repair and that compensatory mechanisms exist for the generation of endogenous RA by other cell types upon proximal tubule injury. ALDH1a2 levels also increase in podocytes, epithelial cells of the glomeruli, after injury, and RA promotes podocyte differentiation. We also review the ability of exogenous, pharmacological doses of RA and receptor selective retinoids to treat numerous kidney diseases, including kidney cancer and diabetic kidney disease, and the emerging genetic evidence for the importance of retinoids and their receptors in maintaining or restoring kidney function after injury. In general, RA has a protective effect on the kidney after various types of injuries (eg. ischemia, cytotoxic actions of chemicals, hyperglycemia related to diabetes). As more research into the actions of each of the three RARs in the kidney is carried out, a greater understanding of the actions of vitamin A is likely to lead to new insights into the pathology of kidney disorders and the development of new therapies for kidney diseases.

Keywords: Acute kidney injury; Chronic kidney disease; Diabetic kidney disease; Fibrosis; Polycystic kidney disease; Proximal tubule injury; Retinoic acid; Retinoic acid receptor.

Figure 1.

Retinoic acid receptors (RARs) α, β, γ bind as heterodimers with RXRs α, β, γ. In the presence of an agonist, RAR/RXR heterodimers bind to and transcriptionally activate or repress genes with RAREs (retinoic acid response elements/enhancers). Shown here is transcriptional activation in the presence of retinoic acid (RA), an endogenous RAR agonist. HDAC, histone deacetylase; HAT, histone acetyl-transferase; SRC-1 (steroid receptor coactivator-1); pol II, RNA polymerase II; other proteins shown are part of the transcription activation complex. RARβ2, one isoform of RARγ, possesses a DR5 RARE in its promoter so one of the RARs is itself a primary target gene activated by RA.

Figure 2.

Metabolism of retinol (vitamin A) to retinyl esters via LRAT (lecithin:retinol acyltransferase), and conversely, metabolism of retinyl esters to retinol by retinyl ester hydrolases (REHs). Metabolism of retinol to retinaldehyde by retinol dehydrogenases, primarily RDH10. Conversely, retinaldehyde can be converted to retinol via DHRS3 + RDH10. Retinaldehyde is metabolized to retinoic acid (RA) by aldehyde dehydrogenases 1a1, 1a2, and 1a3 (formerly called RALDH1,2,3). This is an irreversible reaction. RA can then be further oxidized to 4-hydroxy-RA and 4-oxo-RA by cytochrome P450 26a1, b1, and c1.

Figure 3.

Overview of nephron. Blood travels via the afferent arteriole into a bundle of capillaries called the glomerulus. Materials that are smaller than 100nm are filtered out of the glomerulus and directed into the proximal tubules. The filtered fluid and materials travel through the loop of Henle, consisting of a thin descending loop, a think ascending loop, and a thick ascending loop, the distal tubule, and finally the collecting duct. Many materials, such as sodium, potassium, bicarbonate, and water, are reabsorbed throughout this process. The mesangial cells and podocytes of the glomerulus, and proximal tubule epithelial cells are all known to be responsive to retinoic acid (RA).