Understanding Renal Physiology Leads to Therapeutic Advances in Renal Disease

The final recommendations of the Kidney Research National Dialogue were published in October, 2014 (1). This publication resulted from a multi-year effort, initiated by the Division of Kidney, Urologic, and Hematologic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, to identify important research objectives that would improve knowledge of basic kidney biology and function, and potentially lead to therapeutic advances in the treatment of kidney disease (1). In this report, basic science research was viewed as the central cog that drove advances that could lead to future translation (1). This report followed the publication of 10 commentaries on different facets of research opportunities, one of which was devoted to normal kidney biology (2). Renal physiology was identified as an essential component of defining kidney biology to understand renal disease (2). This commentary concluded that basic physiological studies of hormone receptors, signal transduction pathways, protein trafficking, etc., have the potential to identify previously unrecognized therapeutic targets and elucidate novel regulatory pathways (2).

The wisdom of this conclusion is elegantly articulated in the review of novel therapies for autosomal dominant polycystic kidney disease (ADPKD) by Saigusa and Bell in this issue of Physiology (6). ADPKD is an inherited disorder that leads to the formation of multiple renal cysts and ultimately leads to renal failure (6). ADPKD results from mutations in either the polycystin 1 or polycystin 2 proteins, which result from the PKD1 or PKD2 genes, respectively (6). These proteins are located in the primary cilium (4, 6). A major advance in our understanding of ADPKD came from fundamental physiological research by Praetorius and Spring, who showed that the primary cilium is mechanically sensitive and serves as a flow sensor in renal tubular epithelia (4). They also showed that flow-mediated bending of the primary cilium led to an increase in intracellular calcium and that this effect was mediated by a polycystin (4). These fundamental physiological insights established the critical role of the primary cilium, the polycystin proteins, and signaling pathways in the development of ADPKD.

Building on this fundamental advance, tremendous progress has been made in understanding the physiology of the primary cilium, the proteins and signaling pathways involved, and how it impacts the pathogenesis of ADPKD (6). As discussed by Saigusa and Bell (6), several signaling pathways have been identified as being important in cyst growth, including the mammalian target of rapamycin (mTOR) and the cyclic AMP (cAMP) pathways. Elucidation of these pathways led to clinical trials of rapamycin and tolvaptan; trials that would not have been conducted without the insight provided by the physiological studies. Unfortunately, clinical trials of two different mTOR inhibitors did not show a beneficial effect to slow the progression of cyst development in ADPKD (8, 10). However, the clinical trial of tolvaptan did result in a modest slowing of the progression of ADPKD and was the first clinical trial to do so (9).

The rationale for studying tolvaptan is a direct result of understanding the physiology of the collecting duct. Tolvaptan is a V₂-vasopressin receptor (V₂R) antagonist. V₂Rs are expressed in the kidney collecting duct. Vasopressin binding to this receptor leads to an increase in cAMP, which then increases water reabsorption via aquaporin-2 and urea reabsorption via the UT-A1 and UT-A3 urea transporters (7). Thus knowledge of the physiology of water reabsorption in the collecting duct, combined with the signaling pathways involved in ADPKD, culminated in the successful clinical trial of tolvaptan in ADPKD patients. However, the beneficial effect of tolvaptan was modest, and more work remains to be performed, as discussed by Saigusa and Bell (6).

Another example of the importance of understanding renal physiology as the basis for understanding clinical disease is the role of the epithelial sodium channel, ENaC, in the pathogenesis of Liddle's syndrome, as discussed by Ronzard and Staub in a recent issue of Physiology (5). Liddle's syndrome is a genetic form of hypertension that results from gain of function mutations in ENaC (5). Fundamental physiological research into the regulation of ENaC identified ubiquitylation of ENaC by the ubiquitin-ligase NEDD4-2 as a key regulator of sodium transport, and dysregulation of this pathway can result in hypertension (5). Some Liddle's mutations interfere with the ubiquitylation of ENaC, leading to the constitutive activation of this sodium channel (5). As a result, sodium is continually reabsorbed, leading to hypertension (5). These studies led to the generation of several NEDD4-2 knockout mice, which have somewhat different phenotypes depending on the specific knockout and suggest that more work remains to be done to fully understand the role of NEDD4-2 and ubiquitylation (5).

A role for ubiquitylation in blood pressure has recently been broadened to include regulation of a second sodium transporter: the sodium-chloride co-transporter, NCC (5). Ubiquitylation plays a critical role in regulating NCC abundance (5). However, questions remain regarding the mechanisms by which NCC ubiquitylation and phosphorylation interact (5). One possibility is that NEDD4-2 directly ubiquitylates NCC, thereby reducing NCC surface expression and activity, whereas other factors, such as KLH3/CUL3, may ubiquitylate regulators of NCC, such as the WNKs, and decrease NCC phosphorylation by this indirect mechanism (5). The WNK/SPAK system is a relatively recently discovered pathway that regulates ion transport in the distal nephron, as discussed by Park et al in Physiology in 2012 (3).

These fundamental physiological advances in understanding the pathways regulating sodium (and other ionic) transport in the distal nephron and collecting duct are fascinating and may answer long-standing, unanswered questions regarding normal renal physiology. In addition, elucidating these previously unrecognized regulatory pathways may yield new insights into the pathogenesis of hypertension and suggest novel therapeutic targets.

The rapid progress in understanding the pathogenesis of ADPKD, as reviewed by Saigusa and Bell in this issue of Physiology (6), is an excellent example of how fundamental physiological research can be translated into novel therapeutic strategies. This research led to the first clinical trial to show a benefit in slowing the progression of ADPKD (9). Although there is much more to be done in ADPKD, there are many other promising signaling pathways to be pursued (6). The progress in ADPKD research (6), and the exciting new regulatory pathways involved in sodium transport with their implications for hypertension (3, 5), are clear demonstrations that fundamental kidney physiology serves as a necessary foundation for future translational and clinical studies to advance the treatment of, and possibly prevent, kidney disease (1, 2).