Renal Physiology Physiology of the Renal Interstitium

Long overlooked as the virtual compartment and then strictly characterized through descriptive morphologic analysis, the renal interstitium has finally been associated with function. With identification of interstitial reninand erythropoietin-producing cells, the most prominent endocrine functions of the kidney have now been attributed to the renal interstitium. This article reviews the functional role of renal interstitium. Clin J Am Soc Nephrol 10: 1831–1840, 2015. doi: 10.2215/CJN.00640114 Introduction The physiologic role of the interstitium of the kidney has received comparatively little interest to date. This may partially be attributed to the fact that it was long considered the exclusive domain of descriptive ultrastructural research, which implied that the interstitium was mostly a passive tissue that structurally supported the tubular epithelium (1,2). The renal interstitium received increasing interest in the context of kidney abnormalities, when the role of interstitial fibrosis in progression of CKD became obvious (3–5). Only since transgenic animal studies revealed the physiologic endocrine function of interstitial cells as sources of erythropoietin (Epo) and renin has the physiologic role of the renal interstitium received its due attention. Here we review current knowledge of the form and function of the renal interstitium. Definition and Ultrastructure of the Renal Interstitium The renal interstitium is defined as the intertubular, extraglomerular, extravascular space of the kidney. It is bounded on all sides by tubular and vascular basement membranes and is filled with cells, extracellular matrix, and interstitial fluid (1). Its distribution varies within the kidney; it accounts for approximately 8% of the total parenchymal volume in the cortex and up to 40% in the inner medulla (6,7). The term “renal interstitium” is often inadequately used to refer to the peritubular interstitium (the space between tubules, glomeruli, and capillaries); the periarterial connective tissue and the extraglomerular mesangium are considered specialized interstitia (1). It is debated whether microvessels and capillaries, which are located within the peritubular space, are actually part of the renal interstitium or just run through it (1). Furthermore, lymphatics are considered interstitial constituents (1). The tubular interstitium in the cortex and medulla differ with regard to their cellular constituents, extracellular matrix composition, relative volume, and endocrine function, justifying the consideration of cortical and medullary interstitium as separate entities. The intertubular interstitium harbors dendritic cells, macrophages, lymphocytes, lymphatic endothelial cells (in the cortical intertubular interstitium), and various types of fibroblasts, the hallmark cell type of connective tissues (8). In addition, it is believed that the interstitium plays a role in fluid and electrolyte exchange and insulation (1). Here we focus on fibroblasts and specifically on fibroblasts with endocrine function and their biology in health and disease (other articles have extensively reviewed cellular constituents of the immune system within the renal interstitium [9,10]) (Figure 1). Renal Fibroblasts In general, fibroblasts are flattened cells with extended cell processes; in profile they display a fusiform or spindle-like shape and a flattened nucleus (11). Fibroblasts typically are embedded within the fibrillar matrix of connective tissues and are considered prototypical mesenchymal cells. Renal fibroblasts anastomose with each other, forming a continuous network in cortex and medulla (8). Fibroblasts can acquire an activated phenotype with a relatively large oval nucleus with one or two nucleoli, abundant rough endoplasmatic reticulum, and several sets of Golgi apparatus; this reflects their capacity to synthesize substantial amounts of extracellular matrix constituents (12). Under physiologic conditions, however, adult fibroblasts are relatively inactive, the endoplasmatic reticulum is reduced, and the nucleus is flattened and heterochromatic. On the basis of their appearance, it was assumed that the primary function of renal fibroblasts was to provide structural support to nephrons through deposition of extracellular matrix and through direct cell-cell interactions (1). In addition, fibroblasts play an important role in maintaining vascular integrity in close association with vessels (then typically referred to as vascular smooth muscle cells and pericytes) (13,14). Renal fibroblasts are best known for their role in progression of interstitial fibrosis in progressive CKD because they are principal producers of extracellular matrix (4). Finally, fibroblasts have been identified as sources of Epo and renin in the kidney (15,16). It is obvious that such diverse functions are not fulfilled by one cell type but that renal fibroblasts are instead a heterogeneous cell population with distinct functions. *Department of