PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

Abstract

We investigated the signaling basis for tubule pathology during fibrosis after renal injury. Numerous signaling pathways are activated physiologically to direct tubule regeneration after acute kidney injury (AKI) but several persist pathologically after repair. Among these, transforming growth factor (TGF)-β is particularly important because it controls epithelial differentiation and profibrotic cytokine production. We found that increased TGF-β signaling after AKI is accompanied by PTEN loss from proximal tubules (PT). With time, subpopulations of regenerating PT with persistent loss of PTEN (phosphate and tension homolog) failed to differentiate, became growth arrested, expressed vimentin, displayed profibrotic JNK activation, and produced PDGF-B. These tubules were surrounded by fibrosis. In contrast, PTEN recovery was associated with epithelial differentiation, normal tubule repair, and less fibrosis. This beneficial outcome was promoted by TGF-β antagonism. Tubule-specific induction of TGF-β led to PTEN loss, JNK activation, and fibrosis even without prior AKI. In PT culture, high TGF-β depleted PTEN, inhibited differentiation, and activated JNK. Conversely, TGF-β antagonism increased PTEN, promoted differentiation, and decreased JNK activity. Cre-Lox PTEN deletion suppressed differentiation, induced growth arrest, and activated JNK. The low-PTEN state with JNK signaling and fibrosis was ameliorated by contralateral nephrectomy done 2 wk after unilateral ischemia, suggesting reversibility of the low-PTEN dysfunctional tubule phenotype. Vimentin-expressing tubules with low-PTEN and JNK activation were associated with fibrosis also after tubule-selective AKI, and with human chronic kidney diseases of diverse etiology. By preventing tubule differentiation, the low-PTEN state may provide a platform for signals initiated physiologically to persist pathologically and cause fibrosis after injury.

Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis

“…There is little knowledge with respect to how cellular stress controls the production of profibrotic paracrine molecules. One main factor is the production of TGF-␤ (11,20,21,23,25,26,44,45). The TGF-␤ signaling pathway plays a major role in all fibrotic diseases.…”

Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction

“…TGF-␤ is a pleiotropic cytokine that plays a major role in stimulating extracellular matrix production after UUO, and blocking TGF-␤ has been shown to reduce tubular apoptosis in several models of chronic kidney injury (25,30). It contributes to renal fibrosis by several mechanisms including induced loss of phosphatase tensin homolog that contributes to the failure of regenerating epithelial cells to redifferentiate, thereby causing the retention of proliferative signaling and giving rise to profibrotic peptides (19). TGF-␤ also increases renal fibrosis not only by a direct effect on myofibroblasts but by inducing the production of Notch (1), CTGF (34), and PDGF␤ (40).…”

Cellular and Molecular Mechanisms of AKI

“…In addition, autophagy has been implicated in tubular atrophy, 69,70 a pathologic phenotype in post-AKI tubules that may contribute critically to renal fibrosis. 71 It is also important to elucidate whether and how autophagy contributes to kidney repair after AKI, including fibrosis.…”