In addition to its role as a metabolic waste product, uric acid has been proposed to be an important molecule with multiple functions in human physiology and pathophysiology and may be linked to human diseases beyond nephrolithiasis and gout. Uric acid homeostasis is determined by the balance between production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels, by reabsorbing around 90% of filtered urate, while being responsible for 60–70% of total body uric acid excretion. Defective renal handling of urate is a frequent pathophysiologic factor underpinning hyperuricemia and gout. In spite of tremendous advances over the past decade, the molecular mechanisms of renal urate transport are still incompletely understood. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Understanding these transporters is increasingly important for the practicing clinician as new research unveils their physiology, importance in drug action, and genetic association with uric acid levels in human populations. The future may see the introduction of new drugs that specifically act on individual renal urate transporters for the treatment of hyperuricemia and gout.

Purpose of review-Lipid accumulation in nonadipose tissues is increasingly recognized to contribute to organ injury through a process termed lipotoxicity, but whether this process occurs in the kidney is still uncertain. This article briefly summarizes the normal role of lipids in renal physiology and the current evidence linking excess lipids and lipotoxicity to renal dysfunction.Recent findings-Evidence suggesting that renal lipid accumulation and lipotoxicity may lead to kidney dysfunction has mounted significantly over recent years. Abnormal renal lipid content has been described in a number of animal models and has been successfully manipulated using pharmacologic or genetic strategies. There is some heterogeneity among studies with regard to the mechanisms, consequences, and localization of lipid accumulation in the kidney, explainable at least in part by inherent differences between animal models. The relevance of these findings for human pathophysiology remains to be established.Summary-Current knowledge on renal lipid physiology and pathophysiology is insufficient, but provides a strong foundation and incentive for further exploration. The future holds significant challenges in this area, especially with regard to applicability of research findings to the human kidney in vivo, but also the opportunity to transform our understanding of an array of kidney disorders.

We previously identified a sperm-specific Na ؉ /H ؉ exchanger (sNHE) principally localized to the flagellum. Disruption of the sNHE gene in mice resulted in absolute male infertility associated with a complete loss of sperm motility. Here, we show that the sNHE-null spermatozoa fail to develop the cAMP-dependent protein tyrosine phosphorylation that coincides with the functional maturation occurring upon incubation in capacitating conditions in vitro. Both the sperm motility defect and the lack of induced protein tyrosine phosphorylation are rescued by the addition of cell-permeable cAMP analogs, suggesting that cAMP metabolism is impaired in spermatozoa lacking sNHE. Our analyses of the bicarbonate-dependent soluble adenylyl cyclase (sAC) signaling pathway in sNHE-null sperm cells reveal that sNHE is required for the expression of full-length sAC, and that it is important for the bicarbonate stimulation of sAC activity in spermatozoa. Furthermore, both codependent expression and coimmunoprecipitation experiments indicate that sNHE and sAC associate with each other. Thus, these two proteins appear to be components of a signaling complex at the sperm flagellar plasma membrane. We propose that the formation of this complex efficiently modulates intracellular pH and bicarbonate levels through the rapid and effective control of sAC and sNHE activities to facilitate sperm motility regulation.cAMP ͉ sperm motility

The proximal tubule is critical for whole-organism volume and acid-base homeostasis by reabsorbing filtered water, NaCl, bicarbonate, and citrate, as well as by excreting acid in the form of hydrogen and ammonium ions and producing new bicarbonate in the process. Filtered organic solutes such as amino acids, oligopeptides, and proteins are also retrieved by the proximal tubule. Luminal membrane Na + /H + exchangers either directly mediate or indirectly contribute to each of these processes. Na + /H + exchangers are a family of secondary active transporters with diverse tissue and subcellular distributions. Two isoforms, NHE3 and NHE8, are expressed at the luminal membrane of the proximal tubule. NHE3 is the prevalent isoform in adults, is the most extensively studied, and is tightly regulated by a large number of agonists and physiological conditions acting via partially defined molecular mechanisms. Comparatively little is known about NHE8, which is highly expressed at the lumen of the neonatal proximal tubule and is mostly intracellular in adults. This article discusses the physiology of proximal Na + /H + exchange, the multiple mechanisms of NHE3 regulation, and the reciprocal relationship between NHE3 and NHE8 at the lumen of the proximal tubule. KeywordsAcid-based balance; pH regulation; Volume regulation; Sodium transport; Bicarbonate transport; Chloride transport; Sodium-hydrogen exchange; Sodium-proton exchange Na + /H + exchange in biology Na + /H + exchangers (NHEs) are universally present in prokaryotes, lower eukaryotes, and higher eukaryotes, including fungi, plants, and animals [1]. In prokaryotes, fungi and plants, the transmembrane proton electrochemical gradient (ΔμH + ) energizes the extrusion of Na + from the cytoplasm. Plasma membrane NHEs characterized to date in animal cells utilize the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptinward Na + gradient created by the activity of Na + /K + -adenosine triphosphatase (ATPase) to extrude H + against its electrochemical gradient in an electroneutral fashion.All NHEs are members of the very large superfamily of monovalent cation-proton antiporters (CPA), which is divided phylogenetically in the CPA1, CPA2, and NaT-DC transporter families [1,2]. Nine NHE isoforms (NHE1-9) belonging to the CPA1 family and having different tissue and subcellular distribution (Table 1) have been described to date in the human genome [1,3,4]. In addition, the human genome contains a sperm-specific NHE (a member of the NaT-DC family) with demonstrated NHE activity [1,5,6], as well as two genes termed NHA1 and NHA2 (members of the CPA2 family) which are more closely related to prokaryotic Na + /H + exchangers [1] ( Table 1). The expression and function of NHA2 have been recently confirmed [7,8]. Brett et al. [1] presented an extensive phylogenetic classification of NHEs using 118 eukaryotic NHE genes of the CPA1 family. Based on sequence, cellular location, ion selectivity, and inhibitor specificity, NHEs can be divided into two majo...