Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis

Abstract

Tubular injury has a major etiological role in fibrosis. For many years, this relationship has been dominated by the perception that epithelial cells are transformed into myofibroblasts that proliferate and generate fibrotic matrix-the so-called epithelial-to-mesenchymal transition. Here we focus on mechanisms by which injury to the tubule results in fibrosis because of paracrine mechanisms. Specific injury to the proximal tubule results in inflammation, reversible injury, and adaptive repair if the insult is mild, self-limited in time, and occurs in a background of a normal kidney. Repeated injury, in contrast, leads to maladaptive repair with sustained tubule injury, chronic inflammation, proliferation of interstitial myofibroblasts, vascular rarefaction, interstitial fibrosis, and glomerular sclerosis. During the maladaptive repair process after the renal insult, many tubular cells become arrested in the G2/M phase of the cell cycle. This results in activation of the DNA repair response with the resultant synthesis and secretion of pro-fibrotic factors. Pharmacologic interventions that enhance the movement through G2/M or facilitate apoptosis of cells that otherwise would be blocked in G2/M may reduce the development of fibrosis after kidney injury and reduce the progression of chronic kidney disease.

Keywords: G2/M arrest; acute kidney injury; apoptosis; chronic kidney disease; mitotic stress.

Figures

Figure 1

Adaptive and maladaptive repair after injury. After mild injury self-limited over time and to a kidney that has not sustained prior insults of significance, damaged proximal tubule cells are replaced by surviving proximal tubule cells that dedifferentiate, proliferate, and restore the normal epithelium. By contrast, if the injury is more severe, repeated, or to a kidney that is abnormal at baseline, then the cells that are stimulated to proliferate cannot complete the cell cycle efficiently and often are arrested in G2/M. Apoptosis of these cells may be blocked so that they continue to survive. They then turn on signaling pathways involving Jun N-terminal kinase (JNK), and activate pro-fibrotic gene transcription. This sets off a sequence of events resulting in vascular rarefaction, myofibroblast proliferation, and deposition of collagens and other matrix components in the interstitium.

Figure 2

In vivo cell cycle analysis in acute kidney injury (AKI). Proximal tubule cell cycle distribution (G1, S, and G2/M) of cells in the cell cycle over 42 days after moderate ischemia reperfusion injury (IRI; top left), unilateral ischemia/reperfusion (bottom left), and after administration of aristolochic acid (bottom right; n=3 mice of each time point in each group). AAN, aristolochic acid nephropathy. (Modified from Yang et al.)