Renal fibrosis: Primacy of the proximal tubule

Abstract

Tubulointerstitial fibrosis (TIF) is the hallmark of chronic kidney disease and best predictor of renal survival. Many different cell types contribute to TIF progression including tubular epithelial cells, myofibroblasts, endothelia, and inflammatory cells. Previously, most of the attention has centered on myofibroblasts given their central importance in extracellular matrix production. However, emerging data focuses on how the response of the proximal tubule, a specialized epithelial segment vulnerable to injury, plays a central role in TIF progression. Several proximal tubular responses such as de-differentiation, cell cycle changes, autophagy, and metabolic changes may be adaptive initially, but can lead to maladaptive responses that promote TIF both through autocrine and paracrine effects. This review discusses the current paradigm of TIF progression and the increasingly important role of the proximal tubule in promoting TIF both in tubulointerstitial and glomerular injuries. A better understanding and appreciation of the role of the proximal tubule in TIF has important implications for therapeutic strategies to halt chronic kidney disease progression.

Keywords: Cell cycle; Chronic kidney disease; Epithelial de-differentiation; Metabolism; Proteinuria; Tubulointerstitial fibrosis.

Figure 1. Proximal tubular responses to chronic injury promote tubulointerstitial fibrosis

Chronic injury of diverse etiologies leads to proximal tubular responses that can be both adaptive and maladaptive, depending upon the chronicity and severity of injury. Most uninjured proximal tubule cells are quiescent (cell cycle stage G0), but in injury, the surviving cells reenter the cell cycle to proliferate and replace apoptotic/necrotic cells. Some cycling cells will arrest at either G1 or G2 which protects against damaged cells proliferating and potentially introducing DNA mutations to progeny cells. However, epithelial cells arrested in G2 exhibit a profibrotic phenotype with increased TGF-β and CTGF which promote TIF through paracrine actions. Injured proximal tubule cells de-differentiate as shown by loss of brush border, decreased E.cadherin expression, increased vimentin expression and cytoskeletal changes. Although some de-differentiation may reduce oxygen consumption and promote survival, these changes are also associated with increased production of TGF-β and other profibrotic factors that can act on neighboring myofibroblasts to promote TIF. Injured proximal tubule cells also undergo the unfolded protein response (UPR) and autophagy, both of which may have adaptive or maladaptive effects as shown. Senescence inhibits cell proliferation but enhances production of proinflammatory cytokines as part of the senescence-associated secretory phenotype (SASP). Chronic injury also alters metabolism of proximal tubule cells which normally rely on fatty acid oxidation as the main energy substrate.

Figure 2. The proximal tubule (PT) plays a role in mediating tubular atrophy and TIF in glomerular injury

Glomerular injury can affect the tubulointerstitium by local extension or through increased protein and albumin-bound filtration which is reabsorbed in the proximal tubule. These different mechanisms are not mutually exclusive, and their relative contribution to TIF progression may vary depending upon the etiology of glomerular injury.