Stat3 Controls Tubulointerstitial Communication during CKD

Abstract

In CKD, tubular cells may be involved in the induction of interstitial fibrosis, which in turn, leads to loss of renal function. However, the molecular mechanisms that link tubular cells to the interstitial compartment are not clear. Activation of the Stat3 transcription factor has been reported in tubular cells after renal damage, and Stat3 has been implicated in CKD progression. Here, we combined an experimental model of nephron reduction in mice from different genetic backgrounds and genetically modified animals with in silico and in vitro experiments to determine whether the selective activation of Stat3 in tubular cells is involved in the development of interstitial fibrosis. Nephron reduction caused Stat3 phosphorylation in tubular cells of lesion-prone mice but not in resistant mice. Furthermore, specific deletion of Stat3 in tubular cells significantly reduced the extent of interstitial fibrosis, which correlated with reduced fibroblast proliferation and matrix synthesis, after nephron reduction. Mechanistically, in vitro tubular Stat3 activation triggered the expression of a specific subset of paracrine profibrotic factors, including Lcn2, Pdgfb, and Timp1. Together, our results provide a molecular link between tubular and interstitial cells during CKD progression and identify Stat3 as a central regulator of this link and a promising therapeutic target.

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

“…SASP genes have been shown to play a role in inflammation and in facilitating epithelialto-mesenchymal transition (EMT), two characteristics that are tightly linked to TIF progression (5,6,52). Cytokines such as Il6 are well known to induce Stat3 activation, which is also associated with the progression of TIF (55). In the KS mouse model, we observed that SA-␤-Gal staining was not restricted to the cortex region of the kidney but was apparent throughout the kidney.…”

“…In particular, activation of Stat3 is known to be achieved through phosphorylation of its tyrosine 705 site by receptor tyrosine kinases (RTKs) and has been suggested to have a role in the progression of renal fibrosis (53)(54)(55). Although Stat3 activation from Sav1 loss alone was not obvious by Western blotting (data not shown), histological examination revealed an increase in phospho-…”

Progression of chronic kidney disease: too much cellular talk causes damage

“…Recently, the transcription factor Stat3 was shown to be a critical mediator of epithelial/fibroblast crosstalk leading to TIF by affecting multiple profibrotic genes (52). Transcriptomic analysis from renal tissues revealed that the Jak/Stat pathway was upregulated in human diabetic nephropathy (53).…”

“…PDGFR, FGFR). Tubule-specific deletion of Stat3 in mice protected against TIF after 75% nephron reduction, and this was associated with diminished expression of PDGF-B, Lcn2 (lipocalin/NGAL), and TIMP1(52). As PDGF-B and TIMP-1 have been implicated in fibroblast proliferation (54, 55) and Lcn2 can augment fibroblasts’ production of collagen I (56), Stat3 may mediate pro-fibrotic epithelial/fibroblast crosstalk through multiple targets.…”

The third path of tubulointerstitial fibrosis: aberrant endothelial secretome

“…As noted, our work 34 introduced hypert-IL-6, a receptor-independent gp130/STAT3 activator, as a therapeutic that ameliorates renal fibrosis in two different models, unilateral ureteral obstruction and chronic phase of folic acid nephropathy. Yet, recent publication by Terzi’s group 48 implicates STAT3 activation in the lesion-prone strain of mice, but not in C57BL/6 mice, in progression of fibrosis after nephron reduction. It is not excluded that differences in matrix rigidity and mouse background (our studies were performed using αSMA-GFP transgenic mice on C57BL/6J background) are responsible for disparate results.…”