Exosomes and the kidney: prospects for diagnosis and therapy of renal diseases

Abstract

Exosomes are 40-100 nm membrane vesicles secreted into the extracellular space by numerous cell types. These structures can be isolated from body fluids including urine and plasma. Exosomes contain proteins, mRNAs, miRNAs, and signaling molecules that reflect the physiological state of their cells of origin and consequently provide a rich source of potential biomarker molecules. Aside from diagnostic uses, exosome-mediated transfer of proteins, mRNAs, miRNAs, and signaling molecules offer the promise that they may be used for therapeutic purposes. In this review, we integrate new knowledge about exosomes from outside the field of nephrology with recent progress by renal researchers in order to provide a basis for speculation about how the study of exosomes may affect the fields of nephrology and renal physiology in the next few years.

Figure 1

Exosomes in urine. (a) Electron micrograph of negatively stained urinary exosomes (scale bar, 50 nm). (b) Electron micrograph of a renal inner medullary collecting duct cell (scale bar, 100 nm). Uncoated vesicles (asterisks) and coated vesicles (arrow) are indicated. MVB, multivesicular body. (c) Schematic of urinary exosome formation and release into the urine. AP, adaptor protein; ALIX, ALG-2 interacting protein X; CCP, clathrin-coated pit (clathrin molecules are shown in green); E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin-protein ligase; ESCRT, endosomal sorting complex required for transport; ILVs, intraluminal vesicles; Ub, ubiquitin; Vps4, vacuolar protein sorting 4. (d and e) Electron microscope images of the 17,000 g pellets from pooled normal human urine. Tamm–Horsfall protein (THP) forms long polymeric filaments that are associated laterally to form rope-like structures (d, scale bar, 800 nm and e, depicting the dashed box in d; scale bar, 100 nm). The THP network depicted contains small (40–100 nm) vesicles compatible with exosomes (e, arrowheads).

Figure 2

Mechanisms for exosome-mediated signaling to target cells. Interaction of exosome surface proteins with adhesion molecules or receptors on target cells can initiate a downstream signaling cascade (I). Direct fusion of the exosome membrane with the target cell plasma membrane results in the release of content (RNA, proteins) into the cytoplasm of the target cell (II). Transfer of exosome content to the cytoplasm may also occur after endocytosis and subsequent fusion of the exosome membrane with the endosomal membrane (III).