International Journal of Molecular Sciences Review Sex Differences in Urate Handling Victoria L. Halperin Kuhns * and Owen M. Woodward * Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA * Correspondence: [email protected] (V.L.H.K.); [email protected] (O.M.W.); Tel.: +1-410-706-1754 (V.L.H.K.); +1-410-706-1760 (O.M.W.) Received: 27 May 2020; Accepted: 12 June 2020; Published: 16 June 2020 Abstract: Hyperuricemia, or elevated serum urate, causes urate kidney stones and gout and also increases the incidence of many other conditions including renal disease, cardiovascular disease, and metabolic syndrome. As we gain mechanistic insight into how urate contributes to human disease, a clear sex difference has emerged in the physiological regulation of urate homeostasis. This review summarizes our current understanding of urate as a disease risk factor and how being of the female sex appears protective. Further, we review the mechanisms of renal handling of urate and the significant contributions from powerful genome-wide association studies of serum urate. We also explore the role of sex in the regulation of specific renal urate transporters and the power of new animal models of hyperuricemia to inform on the role of sex and hyperuricemia in disease pathogenesis. Finally, we advocate the use of sex differences in urate handling as a potent tool in gaining a further understanding of physiological regulation of urate homeostasis and for presenting new avenues for treating the constellation of urate related pathologies. Keywords: sex differences; gout; uric acid; serum urate; ABCG2; SLC2A9; URAT1 1. Introduction Understanding the mechanisms of common heritable diseases has long proven to be challenging [1]. One such common human disease is gout, the most common inflammatory arthritis [2]. Gout is caused by the deposition of sodium urate (UA) crystals in the synovial fluid of joints, a process that leads to a cascade of inflammatory responses and extreme discomfort [3]. Precipitation of the weakly soluble UA occurs as the UA levels in the blood and other body fluids rise, termed hyperuricemia. Gout, or podagra, is one of the most well documented human diseases, recognized as early as 2460 BCE by the ancient Egyptians [4]. A staple throughout the development of the civilized world, cases were also noted by Hippocrates and Galen in ancient Greece, with a surge in cases in the 17th and 18th centuries [4] during the industrial revolution, commiserate with rising wealth across the western world. Today, the prevalence of gout is roughly 4% of the population of the United States, Europe, and Southeast Asia [5]. Interestingly, recent research has found that gout is only one of many potential diseases caused or contributed to by hyperuricemia (HUA); HUA is also an independent risk factor for additional pathologies including renal diseases, cardiovascular disease, hypertension, and metabolic syndrome [5–7] (Figure1). As this list of diseases continues to grow, so does the critical need for a deeper understanding of not only how we regulate UA homeostasis, but also the causes of disruptions of these processes. Int. J. Mol. Sci. 2020, 21, 4269; doi:10.3390/ijms21124269 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 21 handling in the kidney, as well as differential effects of pathogenic variants in UA transporter genes, presenting the potential to use sex differences in UA handling as a powerful comparative analysis revealing how these systems are regulated. Here, we review sex differences in UA handling to Int.explore J. Mol. how Sci. 2020 the, 21female, 4269 sex may be protective against the development of UA related diseases and2 of to 20 illustrate the power of using sex differences as a tool. Figure 1. Co-morbidities associated with hyperuricemia, with an emphasis on conditions that can Figure 1. Co-morbidities associated with hyperuricemia, with an emphasis on conditions that can affect the kidneys. Males tend to have higher serum urate levels, and therefore have an increased affect the kidneys. Males tend to have higher serum urate levels, and therefore have an increased risk risk of associated co-morbidities, while females have lower serum urate levels and are protected from of associated co-morbidities, while females have lower serum urate levels and are protected from developing associated co-morbidities. developing associated co-morbidities. A mechanistic picture of the effectors of UA homeostasis has emerged, yet we lack an understanding 2. Urate as a Risk Factor in Disease of how these proteins are regulated. New tools are needed to examine this problem to provide relief for theHUA large is andclinically growing defined population as elevated of hyperuricemic serum UA (SUA, individuals >6mg/dL), [1 ].which Additionally, increases new the risk work of hasthe reinforcedprecipitation the of importance weakly soluble of an UA. ancient Increased observation UA leads [4 ],to theprecipitation male sex isof a monosodium significant risk UA factor crystals, for hyperuricemiawhich can cause and UA gout kidney [8,9], stones where and men gout. are up The to fournumber times of more affected likely individuals to be affected continues than women to climb [5]. 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UrateHUA as is a just Risk one Factor of many in Disease conditions that have observable sex differences, as differing pathologies basedHUA on sex is clinically have been defined observed as elevated in a variety serum UAof fields (SUA, [14>6mg–17]/ dL),including which cardiovascular increases the risk [18 of–21 the], precipitationneurological of[22 weakly–25], immunological soluble UA. 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HUA A prevalencerecent study of 13.3%,determined with strikingthat females differences with inchronic prevalence kidney by disease sex, with (CKD) 19.4% had in men a slower and only decline 7.9% inin womenglomerular [10]. However,filtration rate the risk(GFR), of thelower development risk of progression of HUA increases to end-stage roughly renal four-fold disease for(ERSD), women and after a lower menopause, risk of anddeath postmenopausal compared to age-matched hormone replacement men with therapysimilar reducesmild-to-moderate this risk [11 CKD–13], [42]. providing In diabetic evidence kidney that femaledisease, hormones men tend mayed to contribute demonstrate to the renal protection complications from HUA. roughly 10 years earlier than women [40], whileHUA sex isdifferences just one of manyin obesity-related conditions that kidney have observabledisease [43 sex–45 di] ffdemonstratederences, as diff eringthat pathologiesfemale sex basedhormones on sexmay have safeguard been observed against inworsening a variety pathology of fields [ 14[45].–17 ]Thus, including being cardiovascular female may [have18–21 a], neurologicalprotective effect [22 –on25 ],the immunological kidney, preventing [26–28 women], and renal from diseasesdeveloping [29– the33]. more The severe architecture phenotypes of the femaleobserved kidney in men. is likely All these distinct studies from illustrate that of the the male need kidney for greater [34], givenemphasis women on the have idea a lower of sex blood as a pressurebiological than variable men [46 [35–],48 women], going arebeyond less merely likely tolooking develop at sex acute differences, kidney injury and instead than men examining [36,37], womenthe influence demonstrate of sex on improved various tolerancephysiological to renal and ischemia pathophysiological [38,39], and womenpathways are [49] protected to help from elucidate renal andunderlying cardiovascular mechanisms. disease before menopause as compared to men [40,41]. A recent study determined that females with chronic kidney disease (CKD) had a slower decline in glomerular filtration rate (GFR), lower risk of progression to end-stage renal disease (ERSD), and a lower risk of death compared Int. J. Mol. Sci. 2020, 21, 4269 3 of 20 to age-matched men with similar mild-to-moderate CKD [42]. In diabetic kidney disease, men tended to demonstrate renal complications roughly 10 years earlier than women [40], while sex differences in obesity-related kidney disease [43–45] demonstrated that female sex hormones may safeguard against worsening pathology [45].