The cell biology of renal filtration

Correspondence to Rizaldy P. Scott: [email protected] Abbreviations used in this paper: ESL, endothelial surface layer; FP, foot pro­ cess; GBM, glomerular basement membrane; GEC, glomerular endothelial cell; GFB, glomerular filtration barrier; MC, mesangial cell; PEC, parietal epithelial cell; SD, slit diaphragm. The mammalian kidney orchestrates the excretion of metabolic wastes found in blood, a function intimately related to its essential roles in general fluid homeostasis and osmoregulation. It is also important in the control of blood pressure, synthesis of vitamin D, bone mineralization, and the promotion of erythrocyte development. Despite its modest size (each is approximately the size of a human fist), a mammalian kidney is highly vascularized. A pair of kidneys receives and filters a remarkable volume of blood, estimated to be the equivalent of roughly 20% of total cardiac output (Stein and Fadem, 1978; Munger et al., 2011). In humans, blood filtration by the kidneys generates on average 1 liter of urine per day. Urine is produced and concentrated along the length of nephrons, the basic unit of kidneys (Fig. 1 A). An adult human kidney is known to contain an average of 1 million and up to as many as 2.5 million nephrons (Puelles et al., 2011). A nephron is functionally subdivided into a filtration unit called the renal corpuscle or glomerulus and a segmented tubular resorption compartment (Fig. 1 B). The glomerulus is an assembly of four different cells: the glomerular endothelial cells (GECs), podocytes, mesangial cells (MCs), and parietal epithelial cells (PECs; Figs. 1 C and 2). The word glomerulus is a reference to its intricately tortuous inner capillary tuft formed by GECs, after the Latin word glomus for a ball of yarn (Fig. 2 C). Podocytes are specialized perivascular cells aptly named for their elaborate projections, known as foot processes (FPs) or pedicels, that are intimately wrapped around the exterior of glomerular capillaries (Fig. 2, A and B). GECs and podocytes share a common ECM known as the glomerular basement membrane (GBM). The GECs, the podocytes, and the GBM in between constitute the three distinctive layers of the glomerular filtration barrier (GFB; Fig. 2 E), an elegant sieve that selectively filters blood components, generating a dilute primary urinary filtrate. The mesangium, a stalk-like aggregate of MCs and their ECM called the mesangial matrix, provides the structural reinforcement for the glomerular vasculature. The PECs forms a watertight cuplike enclosure called the Bowman’s capsule. Primary urinary filtrate collects within the Bowman’s capsule and empties through a connected series of epithelial tubules starting from the proximal tubules, the loop of Henle, the distal tubules, and a final collecting duct. The renal tubules of the nephrons and the collecting ducts express various ion and water channels, as well as transporters that help concentrate and adjust the composition of the urinary filtrate by resorption and secretion. This last step is vital for fluid conservation, maintenance of electrolyte balance, and resorption of glucose.