Tubular cross talk in acute kidney injury: a story of sense and sensibility

Abstract

The mammalian kidney is an organ composed of numerous functional units or nephrons. Beyond the filtering glomerulus of each nephron, various tubular segments with distinct populations of epithelial cells sequentially span the kidney from cortex to medulla. The highly organized folding of the tubules results in a spatial distribution that allows intimate contact between various tubular subsegments. This unique arrangement can promote a newly recognized type of horizontal epithelial-to-epithelial cross talk. In this review, we discuss the importance of this tubular cross talk in shaping the response of the kidney to acute injury in a sense and sensibility model. We propose that injury-resistant tubules such as S1 proximal segments and thick ascending limbs (TAL) can act as "sensors" and thus modulate the responsiveness or "sensibility" of the S2-S3 proximal segments to injury. We also discuss new findings that highlight the importance of tubular cross talk in regulating homeostasis and inflammation not only in the kidney, but also systemically.

Keywords: Tamm-Horsfall protein; acute kidney injury; sepsis; tubular cross talk; uromodulin.

Fig. 1.

Spatial relationships between tubules that allow cross talk. The cartoon in A underscores the importance of investigating events at the cellular level to advance our understanding of the global response of the kidney to various stimuli. The cartoon in B depicts the various segments of a nephron and highlights the specific regional distribution of each segment within distinct renal areas. PT, proximal tubule; TDC, thin descending limb; Thin AL, thin ascending limb; mTAL and cTAL, medullary and cortical thick ascending limbs, respectively; DCT, distal convoluted tubule; CCD, cortical collecting duct; mCD, medullary collecting duct; ImCD, inner medullary collecting duct. The image in C is an electron micrograph of the kidney outer medulla (×3,000) showing TAL segments contiguous to S2-S3 proximal segments (arrows), the latter recognized by their typical brush border (BB). Inset: ×50,000 magnification showing an area where the basement membranes of TAL and S3 segments are in direct contact.

Fig. 2.

Tubular cross talk in sepsis-induced acute kidney injury (AKI). In A, intravital 2-photon microscopy reveals that systemically administered fluorescent endotoxin (red) accumulates in S1 tubules via Toll-like receptor 4 (TLR4)-mediated endocytosis. Neighboring S2 segments (but not S1) exhibit severe oxidative stress (H2DCFDA, green). In B, fluorescence microscopy of fixed kidneys shows abundant peroxisomes (PMP70, yellow) in S2 segments (but not S1) under sham conditions. G denotes glomeruli, and green is FITC-phalloidin staining of actin. In C, S2 segments show reduced peroxisomal staining 4 h after endotoxin injury. The cartoon in D depicts S1 as a sensor of danger molecules such as endotoxin in the filtrate. S1 then signals S2 through cytokines such as TNF-α which act on cognate receptors such as TNF-α receptor 1 (TNFR1) present only on S2. In cases of severe stress, this signaling causes early peroxisomal damage and oxidative stress.

Fig. 3.

Tubular cross talk in acute kidney injury due to ischemia-reperfusion. A: low-power magnification (×4 objective) images of kidney sections stained with periodic acid-Schiff (PAS) from mice that underwent sham (left) or renal ischemia-reperfusion injury (IRI; right). Necrotic proximal tubules can be clearly seen after injury, especially in the outer stripe of the outer medulla. B: 2 tubular types (TAL and S3) that are involved in tubular cross talk in the outer medulla. Cross talk between TAL and S3 is probably essential in maintaining kidney homeostasis (health). TAL segments are more resistant to injury compared with S3 segments and can be the source of regenerative factors important for the reparative process in neighboring injured S3 segments.

Fig. 4.

Role of Tamm-Horsfall protein (THP) in tubular cross talk during AKI. A: graph summarizing the expression of THP after ischemic injury based on published studies. AKI is a state of THP deficiency observed especially at the peak of injury. Recovery from AKI is associated with increased expression of THP, which is needed to suppress inflammatory signaling in the kidney. B: tubular cross talk model, supporting that THP is essential in suppressing proinflammatory signaling in neighboring S3 proximal tubules. THP regulates the expression of CXCL-2 and IL-23, both of which can stimulate neutrophil influx into the kidney. In addition, both cytokines are downstream of NF-κB, which suggests that THP regulates the activation of NF-κB.

Fig. 5.

Sense and sensibility model of tubular cross talk. S1 and TAL segments sense kidney stress and are resistant to injury. S1 is a sensor of systemic stress through monitoring of the filtrate. TAL segments are sensors of endogenous kidney stress. Both sensors signal to the S2-S3 segments. The S2-S3 segments release various cytokines that can shape the response of the kidney to injury, but can also affect distant organs through an effect on granulopoiesis by activating the IL-23/IL-17 axis. Under physiological stress, this system maintains homeostasis. However, with severe injury, the S2-S3 segments are particularly susceptible to damage, probably due to failure of quenching the increased load of oxidative stress.