A clear pathway to tubulointerstitial disease: is an exclusive focus on fibrosis justified?

Abstract

Tubulointerstitial accumulation of matrix proteins in human kidney biopsies is the best predictor of renal survival. In this issue of the JCI, Yen-Ting Chen et al. elegantly show that an endoplasmic reticulum resident protein, thioredoxin domain containing 5 (TXNDC5), is a key mediator of experimental kidney fibrosis. The researchers used knockout or conditional knockout animals to reduce Txndc5 expression, which reduced the accumulation of fibrous tissue in three models of chronic kidney disease (CKD), including unilateral ureteral obstruction, unilateral ischemia reperfusion injury, and folic acid nephropathy. More importantly, the studies demonstrate that the activated fibroblasts are almost exclusively responsible for producing matrix proteins. The study also showed that reducing Txndc5 in mice after tubulointerstitial fibrosis (TIF) was established mitigated the fibrosis. These experiments have obvious clinical importance but warrant caution because a key question remains unanswered. The impact of reducing TXNDC5 on renal function itself, the very heart of CKD, demands further exploration.

Figure 1. Multicompartmental model of proximal tubule injury underlying chronic kidney disease.

The proximal tubule responds to chronic injury with adaptive and maladaptive outcome. Normally, proximal tubule cells are quiescent with low rates of entry in the cell cycle (G₀). When injured, proximal tubule cells enter the cell cycle at higher rates but fail to progress to mitosis. Damage to DNA and the endoplasmic reticulum provokes cyclin kinase inhibitors (CKIs) to block proximal tubule cells at several stages of the cell cycle (10). Injured proximal tubule cells dedifferentiate as they lose their brush border, have decreased E-cadherin expression and increased vimentin expression, and lose transport proteins. These dedifferentiated cells are the source of many genes underpinning repair or activating neighboring cells, including the immediate early genes, such as the mitogen activated kinases that could either aide or impair repair. Yen-Ting Chen et al. showed that fibroblasts from fibrotic mouse kidneys upregulated TXNDC5, which was controlled by the ATF6-dependent ER stress pathway (1). Chronic injury alters the proximal tubule cell metabolism by inhibiting mitochondrial fatty acid oxidation, generating superoxide, increasing potentially damaging triglycerides, and provoking ferroptotic cell death. Injured proximal tubule cells also undergo the unfolded protein response and autophagy, which arrests the cell cycle and promotes senescence. Each injured compartment may provoke secretion of inflammatory mediators that may attract or activate particular cells to amplify or repair the injury. The balance between adaptive and maladaptive pathways depends on the particular insult as well as its duration and severity.