Cell culture models and animal models for studying the patho-physiological role of renal aquaporins

Abstract

Aquaporins (AQPs) are key players regulating urinary-concentrating ability. To date, eight aquaporins have been characterized and localized along the nephron, namely, AQP1 located in the proximal tubule, thin descending limb of Henle, and vasa recta; AQP2, AQP3 and AQP4 in collecting duct principal cells; AQP5 in intercalated cell type B; AQP6 in intercalated cells type A in the papilla; AQP7, AQP8 and AQP11 in the proximal tubule. AQP2, whose expression and cellular distribution is dependent on vasopressin stimulation, is involved in hereditary and acquired diseases affecting urine-concentrating mechanisms. Due to the lack of selective aquaporin inhibitors, the patho-physiological role of renal aquaporins has not yet been completely clarified, and despite extensive studies, several questions remain unanswered. Until the recent and large-scale development of genetic manipulation technology, which has led to the generation of transgenic mice models, our knowledge on renal aquaporin regulation was mainly based on in vitro studies with suitable renal cell models. Transgenic and knockout technology approaches are providing pivotal information on the role of aquaporins in health and disease. The main goal of this review is to update and summarize what we can learn from cell and animal models that will shed more light on our understanding of aquaporin-dependent renal water regulation.

Renal Membrane Transport Proteins and the Transporter Genes

“…In this way, high sodium diet favors urinary sodium concentration [9]. AQP2 has a role in hereditary and acquired diseases affecting urineconcentrating mechanisms [10]. AQP2 regulates antidiuretic action of arginine vasopressin (AVP).…”

Age-related changes in renal AQP3 and AQP4 expression in Sprague Dawley rats

“…Conversely, AQP4 null mice show only a mild deficit in urinary concentrating ability. In addition, AQP3/ AQP4 double-knockout mice show more severe polyuria than single AQP3 knockout mice (Ma et al, 2000;Tamma et al, 2012;Marlar et al, 2014), indicating the existence of a compensatory mechanism between AQP3 and AQP4 (Marlar et al, 2014).…”

“…AQP2 is the main target of vasopressin (AVP), which regulates water permeability in the collecting duct (Nejsum et al, 2001;BonillaFelix, 2004). AVP regulates AQP2 via short-term and long-term regulatory mechanisms, which are fundamentally different (Nielsen and Agre, 1995;Poulsen et al, 2013) AQP2 null mice fail to thrive and die postnatally as a result of excessive extracellular fluid loss, indicating that the concentration of urine is dependent on the presence of AQP2 (Tamma et al, 2012;Xing et al, 2014). AQP3 and AQP4 are localized to the basolateral plasma membranes of principal cells in the connecting tubule and collecting duct (Murillo-Carretero et al, 1999;Nielsen et al, 1999;Tamma et al, 2012;Kortenoeven and Fenton, 2014) and provide potential pathways of water reabsorption via AQP2 (Wang et al, 2002;Nishimura and Yang, 2013;Koetenoeven and Fenton, 2014;Marlar et al, 2014).…”

“…AVP regulates AQP2 via short-term and long-term regulatory mechanisms, which are fundamentally different (Nielsen and Agre, 1995;Poulsen et al, 2013) AQP2 null mice fail to thrive and die postnatally as a result of excessive extracellular fluid loss, indicating that the concentration of urine is dependent on the presence of AQP2 (Tamma et al, 2012;Xing et al, 2014). AQP3 and AQP4 are localized to the basolateral plasma membranes of principal cells in the connecting tubule and collecting duct (Murillo-Carretero et al, 1999;Nielsen et al, 1999;Tamma et al, 2012;Kortenoeven and Fenton, 2014) and provide potential pathways of water reabsorption via AQP2 (Wang et al, 2002;Nishimura and Yang, 2013;Koetenoeven and Fenton, 2014;Marlar et al, 2014). AQP3 is located in the cortical and outer medullary collecting ducts and AQP4 is located in the inner medullary collecting duct membrane (Terris et al, 1995;Verkman, 1998;Nielsen et al, 2002;Kim et al, 2005;Verkman, 2006;Nishimura and Yang, 2013) AQP3 is regulated by long-term AVP stimulation (Terris et al, 1995;Yang et al, 2013;Xing et al, 2014) and extracellular pH (Zelenina et al, 2003;Castle, 2005).…”

“…In addition to water, AQP3 also transports glycerol and urea (King and Agre, 1996;Lee et al, 1997;Kuwahara et al, 1997) AQP4 enables water permeation in the basolateral plasma membrane of the rat inner medullary collecting duct (Ma et al, 2000). Deletion of AQP3 in mice leads to polyuria and down regulation of AQP2 (Ma et al, 2000;Tamma et al, 2012) because of severe defects in the urinary concentrating ability. Conversely, AQP4 null mice show only a mild deficit in urinary concentrating ability.…”