Table 1.
Genetic manipulation of Wnt/β-catenin signaling and its effects (direct and indirect) on renal tubular epithelia. Studies that have genetically altered the Wnt/β-catenin signaling pathway either directly in renal tubules or indirectly (with effects on renal tubules) are listed with the injury models used, response of the conditional knockout or transgenic mouse, putative mechanism, and the appropriate reference. Of note, while the response noted is in vivo, the mechanism may be based on in vitro experiments. Studies manipulating Wnt/β-catenin signaling in the glomerular epithelial cells (podocyte, parietal epithelium) were beyond the scope of this review. Several additional studies have looked at Wnt/β-catenin in the injured kidney using systemic inhibitors, but these were not included, as they do not.
| Manipulation of Wnt/β-Catenin Pathway | Injury Model | Response | Mechanism | Ref. |
|---|---|---|---|---|
| Deletion of Wnt7 in macrophages | I/R | Increased renal tubular apoptosis | Cell cycle progression and basement membrane repair | [32] |
| Tubule specific ablation of β-catenin | I/R and folic acid | Greater mortality and tubular apoptosis, lower renal function | Increased pro-apototic Bax and p53, decreased pAkt and survivin | [33] |
| GSK-3β inhibition in proximal tubule | HgCl2 | Reduced tubular apoptosis and mortality, improved function | Increased cell proliferation and cyclin D1/c-Myc | [35] |
| Wnt1 overexpression by proximal tubule | None | Increased interstitial fibrosis | Increased paracrine myofibroblast signaling, no epithelial injury | [38] |
| Tubule specific ablation of β-catenin | UUO | No effect on fibrosis, reduced epithelial de-differentiation, increased fibroblast survival | Fibroblast survival due to reduced MMP-7-dependent FasL induction | [39] |
| Proximal tubule specific β-catenin stabilization (cells also lack TGF-β receptor) | Aristolochic acid | Reduced tubulointerstitial fibrosis, improved renal function, and reduced tubular injury | Reduced susceptibility to apoptosis and decreased G2/M arrest | [40] |
| Mutation of Frizzled4 receptor, primarily expressed in epithelia | I/R | Persistent epithelial injury | Increased apoptosis | [32] |
I/R: ischemia/reperfusion; GSK: glycogen sythase kinase; UUO: unilateral ureteral obstruction; MMP-7: matrix metalloproteinase-7; TGF-β: transforming growth factor-β.