Diurnal Regulation of Renal Electrolyte Excretion: The Role of Paracrine Factors

Abstract

Many physiological processes, including most kidney-related functions, follow specific rhythms tied to a 24-h cycle. This is largely because circadian genes operate in virtually every cell type in the body. In addition, many noncanonical genes have intrinsic circadian rhythms, especially within the liver and kidney. This new level of complexity applies to the control of renal electrolyte excretion. Furthermore, there is growing evidence that paracrine and autocrine factors, especially the endothelin system, are regulated by clock genes. We have known for decades that excretion of electrolytes is dependent on time of day, which could play an important role in fluid volume balance and blood pressure control. Here, we review what is known about the interplay between paracrine and circadian control of electrolyte excretion. The hope is that recognition of paracrine and circadian factors can be considered more deeply in the future when integrating with well-established neuroendocrine control of excretion.

Keywords: circadian rhythms; clock genes; endothelin; potassium; purinergic receptors; sodium.

Figure 1

Approximate time of day when a variety of major renal excretory systems reach their maximum level. Minimums generally occur at the opposite side of this 24-h clock. Abbreviations: ADH, antidiuretic hormone; GFR, glomerular filtration rate.

Figure 2

Persistence of circadian urine flow despite having a 12-h eating and sleeping pattern in healthy volunteers (10).

Figure 3

Simplified view of the core circadian clock. Bmal1 and Clock heterodimerize before binding to E-box elements on the promoters of a wide range of genes including Per and Cry. Per and Cry proteins then heterodimerize before then inhibiting Bmal1 and Clock binding to the E-box. However, this translocation is dependent upon phosphorylation by CK1δ/ε. Figure based on a variety of sources but primarily Reference . Abbreviations: EDN1, endothelin-1; ENaC, epithelial sodium channel alpha subunit or SCNN1A; NHE3, sodium/hydrogen exchanger 3 or SLC9A3; OAT3, organic anion transporter 3 or SLC22A8; REN1, renin 1; SGLT1, sodium-glucose cotransporter 1 or SLC5A1.

Figure 4

Approximate rhythm of mRNA expression for major Na⁺ transporters in the mouse kidney. Figure based on the Circadian Expression Profiles Database (CircaDB) originally established by Panda et al. (13). Abbreviations: αENaC, alpha epithelial sodium channel alpha subunit; NHE3, sodium/hydrogen exchanger 3; NKCC, potassium chloride channel; SGLT2, sodium-glucose cotransporter 2.

Figure 5

Approximation of blood pressures over the course of 24 h in mice with various clock gene knockouts (KO) compared to wild types (wt). All panels are based on 12:12 light:dark conditions while maintained on standard rodent diets. Red arrows depict significant differences in KO versus wt in light and dark conditions. Per1 KO strains are shown for two different genetic backgrounds, C57Bl/6 and 129/sv. For Clock, there is a mutant strain that has a non-functional protein expressed and a traditional KO strain. Kidney Bmal1 specific KO include the Pax8-Cre that is specific for the entire nephron and the Ren1-Cre that is specific for cells expressing renin, which includes juxtaglomerular cells as well as renal epithelium.

Figure 6

Primary site of action of major paracrine/autocrine factors in the nephron. Although these and other paracrine factors may have other sites of action, these have been established in vivo. Abbreviations: ET-1, endothelin 1; NO, nitric oxide; PGE2, prostaglandin E2.