Ion Channels in Renal Disease

The cells of the kidney contain many specialized ion channels and transporters, which act in concert to regulate volume and ionic concentration by absorption or secretion of ions into the urine. Each region of the kidney involved in filtration and concentration of ions expresses a particular subset of ion channels. Together, these ion channels ensure appropriate electrolyte homeostasis. However, a number of hereditary and genetic mutations render these channels mis-or non-functional. Mutations to one or more of these ion channels are associated with a variety of symptoms including proteinuria, progressive loss of renal function, and renal hypertension. The progressive loss of renal function, culminating in end-stage renal disease is typically treated by dialysis or transplantation. End-stage renal disease is an increasing health problem, both in terms of prevalence and economic burden. The scope of this review is to first provide a general overview of the kidney and function, and then specifically address the ion channels that, when mutated, lead to kidney disease. 1.1. Physiology of renal ion handling The basic unit of the kidney is the nephron, and its function is to balance the ionic composition of the blood by filtering the blood, retrieving the necessary ions, secreting excess ions, and conserving water to concentrate the urine. Renal disease can be a manifestation of genetic mutations to renal channels (the focus of this review) or transporters (not discussed here, but there are many excellent reviews1). The correlation between distribution of a particular ion channel and its function for the kidney is a critical factor in the localization of disease. Most of these ion channels are tightly regulated and linked to a particular region of the nephron. Malfunctions in these channels can lead to impaired absorption of ions, and ultimately alter the osmotic balance in the kidney, with consequences on the ionic balance of the blood and tissues of the body. Specifically, mutations to a particular ion channel can have large effects beyond the kidney, as the ionic balance regulates a plethora of cotransporters required for transport of additional ions and other nutrients as well. The nephron can be divided into the renal corpuscle, responsible for initial filtration, and the renal tubule, responsible for secretion and reabsorption of ions. The outline below describes the path of fluid filtration and concentration through the kidney, and identifies the ion channels that will be the subject of further discussion in Section 2. The order in which the ion channels are discussed in Section 2 reflects the fluid path through the kidney (Table 1). Figure 1 provides a schematic of the kidney filtration and concentration apparatus, and localizes the ion channels that will be addressed in this review. Open in a separate window Figure 1 Overview of the kidney nephron and the distribution of ion channels discussed in this review. Fluid enters the glomerulus, then down the convoluted proximal tubule. After passing through the loop of Henle, the fluid is further concentrated in the distal convoluted tubule, and then the fluid reaches the collecting duct. See text for details.