International Journal of Molecular Sciences Review Aquaporins in Renal Diseases Jinzhao He and Baoxue Yang * State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100038, China; [email protected] * Correspondence: [email protected]; Tel.: +86-10-82805622 Received: 25 December 2018; Accepted: 14 January 2019; Published: 16 January 2019 Abstract: Aquaporins (AQPs) are a family of highly selective transmembrane channels that mainly transport water across the cell and some facilitate low-molecular-weight solutes. Eight AQPs, including AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11, are expressed in different segments and various cells in the kidney to maintain normal urine concentration function. AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation. Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus. Studies with animal models show AQPs are related to acute kidney injury and various chronic kidney diseases, such as diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma. Experimental data suggest ideal prospects for AQPs as biomarkers and therapeutic targets in clinic. This review article mainly focuses on recent advances in studying AQPs in renal diseases. Keywords: aquaporin; vasopressin; nephrogenic diabetes insipidus; acute kidney injury; diabetic nephropathy; polycystic kidney disease; renal cell carcinoma 1. Introduction Aquaporins (AQPs) are a family of highly selective transmembrane channels that mainly transport water across the cell and some facilitate low-molecular-weight solutes. AQPs consist of 13 members (AQP0–AQP12) in mammals and are widely distributed in various tissues and organs. According to their primary structure, they have been classified into three subfamilies. Water-selective AQPs include AQP0, AQP1, AQP2, AQP4, AQP5, AQP6, and AQP8, which are also known as orthodox aquaporins. Aquaglyceroporins, including AQP3, AQP7, AQP9, and AQP10, are permeable to water and some small uncharged solutes, such as glycerol and urea [1,2]. AQP3 AQP8, and AQP9 have been demonstrated to transport hydrogen peroxide (H2O2) in mammalian cells [3,4]. The third subfamily named superaquaporins, including AQP11 and AQP12 [5], has low homology at its amino acid level with other classical AQPs. Due to a wide spectrum of pathophysiological function in balancing water homeostasis, modulating intracellular signaling, and regulating cell proliferation and oxidative stress response, AQPs have been proven to participate in renal diseases, dermatosis, bowel disease, and cancer [3,6–8]. This review article mainly focuses on the effect of AQPs in kidney diseases. 2. Expression of Physiological Function of AQPs in the Kidney In the kidney, eight AQPs, including AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11, are expressed in different segments and various cells to maintain normal urine concentration function, tissue development and substance metabolism [9,10] (Figure1). Int. J. Mol. Sci. 2019, 20, 366; doi:10.3390/ijms20020366 www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci. 20192019, ,2020, ,x 366 FOR PEER REVIEW 2 2of of 16 16 Figure 1. Expression localization of AQPs in kidney. AQP1 is located in proximal tubule, descending Figure 1. Expression localization of AQPs in kidney. AQP1 is located in proximal tubule, descending thin limbs of Henle, and vasa recta; AQP2, AQP3, AQP4, AQP5 and AQP6 are in the collecting duct; thin limbs of Henle, and vasa recta; AQP2, AQP3, AQP4, AQP5 and AQP6 are in the collecting duct; AQP7 and AQP11 are expressed in proximal tubule. AQP7 and AQP11 are expressed in proximal tubule. AQP1 is the first discovered water channel, and is located in the apical and basolateral plasma AQP1 is the first discovered water channel, and is located in the apical and basolateral plasma membrane of the proximal tubule, descending thin limbs of Henle, and descending vasa recta to membrane of the proximal tubule, descending thin limbs of Henle, and descending vasa recta to mediate water reabsorption [11]. AQP1 is a highly selective water-permeable channel. Mice defective mediate water reabsorption [11]. AQP1 is a highly selective water-permeable channel. Mice defective with AQP1 exhibit polyuria, indicating its key role in the formation of hypertonicity [12,13]. with AQP1 exhibit polyuria, indicating its key role in the formation of hypertonicity [12,13]. AQP2 is one of the most important channel proteins involved in regulating urine concentration, AQP2 is one of the most important channel proteins involved in regulating urine concentration, and is located at the apical membrane of principal cells in the collecting duct [14]. The water and is located at the apical membrane of principal cells in the collecting duct [14]. The water reabsorption function of AQP2 is mainly regulated by arginine vasopressin (AVP) via increasing reabsorption function of AQP2 is mainly regulated by arginine vasopressin (AVP) via increasing intracellular production of cyclic adenosine monophosphatase (cAMP) and further phosphorylation intracellular production of cyclic adenosine monophosphatase (cAMP) and further phosphorylation of AQP2 at Ser256 and Ser269 to stimulate the intracellular trafficking of AQP2 to the plasma of AQP2 at Ser256 and Ser269 to stimulate the intracellular trafficking of AQP2 to the plasma membrane [15–17] (Figure2). Besides AVP, researchers have demonstrated that activation of bile membrane [15–17] (Figure 2). Besides AVP, researchers have demonstrated that activation of bile acid acid receptor TGR5 and hydrogen sulfide (H2S) stimulates the expression of AQP2 via cAMP-protein receptor TGR5 and hydrogen sulfide (H2S) stimulates the expression of AQP2 via cAMP-protein kinase A (PKA) signaling pathway and attenuates the defection of urinary concentration in kinase A (PKA) signaling pathway and attenuates the defection of urinary concentration in mice mice [18,19]. In fact, AQP2 expression, phosphorylation, and trafficking are not only activated [18,19]. In fact, AQP2 expression, phosphorylation, and trafficking are not only activated by canonical by canonical AVP/cAMP/PKA signaling but also other signaling. Erlotinib, an epidermal growth AVP/cAMP/PKA signaling but also other signaling. Erlotinib, an epidermal growth factor receptor factor receptor (EGFR) inhibitor, has been reported to enhance AQP2 accumulation in plasma (EGFR) inhibitor, has been reported to enhance AQP2 accumulation in plasma membrane and water membrane and water reabsorption through increasing phosphorylation of AQP2 at Ser-256 and Ser-269 reabsorption through increasing phosphorylation of AQP2 at Ser-256 and Ser-269 and reducing and reducing endocytosis of AQP2 without affecting classic PKA signaling [20]. Administration endocytosis of AQP2 without affecting classic PKA signaling [20]. Administration of Wnt5a of Wnt5a alleviated decreased urine osmolality and upregulation of AQP2 via activation of alleviated decreased urine osmolality and upregulation of AQP2 via activation of calcium/calmodulin/calcineurin signaling [21]. Additionally, the expression of AQP2 can be regulated calcium/calmodulin/calcineurin signaling [21]. Additionally, the expression of AQP2 can be by several transcription factors, such as AP-1, NF-κB, and NFAT [22]. cAMP-responsive element regulated by several transcription factors, such as AP-1, NF-κB, and NFAT [22]. cAMP-responsive binding protein (CREB) has been recognized as a major regulator of AQP2 expression. However, recent element binding protein (CREB) has been recognized as a major regulator of AQP2 expression. evidence identified that C/EBPβ is pertinent to transcriptional regulation of AQP2 and the relationship However, recent evidence identified that C/EBPβ is pertinent to transcriptional regulation of AQP2 between CREB and AQP2 is indirect [23]. Notably, normal expression of AQP2 in apical plasma and the relationship between CREB and AQP2 is indirect [23]. Notably, normal expression of AQP2 membrane plays a critically determinant role in renal urine concentration and body water balance. in apical plasma membrane plays a critically determinant role in renal urine concentration and body Deletion or mutation of the AQP2 gene causes severe water disorders and triggers the initiation of water balance. Deletion or mutation of the AQP2 gene causes severe water disorders and triggers the nephrogenic diabetes insipidus (NDI). Urinary excretion of AQP2 has been recognized as a useful initiation of nephrogenic diabetes insipidus (NDI). Urinary excretion of AQP2 has been recognized marker for diagnosis of renal diseases [24]. as a useful marker for diagnosis of renal diseases [24]. Int. J. Mol. Sci. 2019, 20, 366 3 of 16 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 16 Figure 2. Figure 2.Schematic Schematic summary summary of mainof main regulatory regulatory mechanisms mechanisms of AQP2. of AVPAQP2. binding AVP tobinding V2R stimulates to V2R the activation of canonical cAMP/PKA signaling and increases the expression and phosphorylation stimulates the activation of canonical cAMP/PKA signaling and increases the expression and of AQP2 at S256 and S269, leading to the apical membrane trafficking of AQP2. Activation of TGR5 phosphorylation of AQP2 at S256 and S269, leading to the apical membrane trafficking