Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by large fluid-filled cysts and progressive deterioration of renal function necessitating renal replacement therapy. Previously, we generated a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model and showed that inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Therefore, we hypothesized that injury-induced tubular epithelial cell proliferation may accelerate cyst formation in the kidneys of adult Pkd1-deletion mice. Mice were treated with the nephrotoxicant 1,2-dichlorovinyl-cysteine (DCVC) after Pkd1-gene inactivation, which indeed accelerated cyst formation significantly. After the increased proliferation during tissue regeneration, proliferation decreased to basal levels in Pkd1-deletion mice just as in DCVC-treated controls. However, in severe cystic kidneys, 10-14 weeks after injury, proliferation increased again. This biphasic response suggests that unrestricted cell proliferation after injury is not the underlying mechanism for cyst formation. Aberrant planar cell polarity (PCP) signaling and increased canonical Wnt signaling are suggested to be involved in cyst formation. Indeed, we show here that in Pkd1 conditional deletion mice expression of the PCP component Four-jointed (Fjx1) is decreased while its expression is required during tissue regeneration. In addition, we show that altered centrosome position and the activation of canonical Wnt signaling are early effects of Pkd1-gene disruption. This suggests that additional stimuli or events are required to trigger the process of cyst formation. We propose that during tissue repair, the integrity of the newly formed Pkd1-deficient cells is modified rendering them susceptible to subsequent cyst formation.

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

“…For the renal cystic phenotype, we previously showed that the renal injury is a trigger that strongly accelerates the polycystic kidney disease. 31 Extensive isometric myographic analysis did also reveal that no difference in response to KCl, acetylcholine, phenylephrin, U46619 or serotonin was observed in young mice (11 weeks) or in older mice (40 weeks), in heterozygous or in homozygous animals with a selective disruption of Pkd1 in SMCs. Only the 40-week-old heterozygous Pkd1 del/ þ mice, which carry a deletion allele in all cells, show a significant increase in vascular contractility in response to phenylephrin.…”

LRP5 variants may contribute to ADPKD

“…The role of canonical Wnt signaling in ADPKD has been an area of research. [20][21][22][23][24][25] Increased canonical Wnt signaling [20][21][22] and diminished signal activation or stable β-catenin [23][24][25] that lead to an opposite effect of planar cell polarity/noncanonical signaling have been reported in different ADPKD mouse models. These data suggest renal cystogenesis is initiated by imbalance between canonical and planar cell polarity/ non-canonical signaling.…”

Loss of Primary Cilia Upregulates Renal Hypertrophic Signaling and Promotes Cystogenesis

“…The advantage of this model is that the remaining kidney is untouched and there is no damage to this kidney because of ischemia or nephrotoxins. Previous studies used induction of renal injury with ischemia-reperfusion or a nephrotoxin 9,15,16 to assess accelerated cyst formation. These models involve the repair of renal injury, which is a complex process that involves repopulating damaged renal tubules with regenerated cells.…”

“…Other studies have shown accelerated cyst formation after ischemic or nephrotoxic kidney injury. 9,15,16 However, recovery from acute kidney injury is a multifactorial process including loss of normal renal architecture, disruption of cell-tomatrix and cell-to-cell interactions, necrosis, apoptosis, and recruitment of a myriad of hormones and autocoids. 17 Recent studies 18,19 have indicated that the mammalian target of rapamycin (mTOR) 20 may be one important factor that mediates the hypertrophic response to unilateral nephrectomy.…”