Evolution of urea transporters in vertebrates: adaptation to urea's multiple roles and metabolic sources

Abstract

In the two decades since the first cloning of the mammalian kidney urea transporter (UT-A), UT genes have been identified in a plethora of organisms, ranging from single-celled bacteria to metazoans. In this review, focusing mainly on vertebrates, we first reiterate the multiple catabolic and anabolic pathways that produce urea, then we reconstruct the phylogenetic history of UTs, and finally we examine the tissue distribution of UTs in selected vertebrate species. Our analysis reveals that from an ancestral UT, three homologues evolved in piscine lineages (UT-A, UT-C and UT-D), followed by a subsequent reduction to a single UT-A in lobe-finned fish and amphibians. A later internal tandem duplication of UT-A occurred in the amniote lineage (UT-A1), followed by a second tandem duplication in mammals to give rise to UT-B. While the expected UT expression is evident in excretory and osmoregulatory tissues in ureotelic taxa, UTs are also expressed ubiquitously in non-ureotelic taxa, and in tissues without a complete ornithine-urea cycle (OUC). We posit that non-OUC production of urea from arginine by arginase, an important pathway to generate ornithine for synthesis of molecules such as polyamines for highly proliferative tissues (e.g. testis, embryos), and neurotransmitters such as glutamate for neural tissues, is an important evolutionary driving force for the expression of UTs in these taxa and tissues.

Physiological and molecular ontogeny of branchial and extra-branchial urea excretion in posthatch rainbow trout (Oncorhynchus mykiss)

“…It is possible that differences in arginine content between the yolk and commercial trout pellets and in overall feeding rates, both of which were not measured in the present study, could have contributed to an increased urea load following the onset of exogenous feeding. Recently, it has been suggested that the expression of UTs in nonureagenic tissues may be integral in limiting the internal accumulation of urea, preventing a "back up" of the arginase system via a mass action effect (13). This notion is supported by the observation that when 55 dph trout were loaded with exogenous urea, gill UT gene expression increased (Fig.…”

“…In most fish species, urea transport across epithelia occurs via a facilitated diffusion urea transporter (UT) (15,33,34). There are three UT isoforms in fish: UT-A, UT-C, and UT-D (13). In zebrafish, UT-A is expressed in the gills, while both UT-A and UT-C are expressed in the kidney (13).…”

“…There are three UT isoforms in fish: UT-A, UT-C, and UT-D (13). In zebrafish, UT-A is expressed in the gills, while both UT-A and UT-C are expressed in the kidney (13). Furthermore, using in situ hybridization, UT-A mRNA was demonstrated to be present in the yolk sac skin, gill, liver, and kidney of posthatch (4 -8 days postfertilization) larval zebrafish (1).…”

Amphibious fishes: evolution and phenotypic plasticity

“…The hepatic OUC is induced in lungfish and in the Singhi catfish Heteropneustes fossilis during terrestrial sojourns, and urea accumulates in the tissues until water returns (Table 4). During reimmersion of lungfish, the facilitated urea transporter is up-regulated to promote rapid elimination of urea (Wood et al, 2005;Hung et al, 2009;LeMoine and Walsh, 2015). In contrast, a few amphibious species simply store glutamine during air exposure (Table 4); this can be easily degraded by glutaminase to glutamate and NH 4 + when water returns.…”

Urea transport and clinical potential of urearetics

“…A recent review analyzed the evolution of urea transporters in vertebrates (36). This analysis showed that three homologues, UT-A, UT-C, and UT-D, evolved from a single ancestral UT in piscine lineages, followed by a reduction to a single UT-A (36).…”