Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

Abstract

In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury. However, this hypothesis is primarily on the basis of animal studies, in which the gene is inactivated simultaneously in large percentages of kidney cells. To mimic human ADPKD in mice more precisely, we reduced the percentage of Pkd1-deficient kidney cells to 8%. Notably, no pathologic changes occurred for 6 months after Pkd1 deletion, and additional renal injury increased the likelihood of cyst formation but never triggered rapid PKD. In mildly affected mice, cysts were not randomly distributed throughout the kidney but formed in clusters, which could be explained by increased PKD-related signaling in not only cystic epithelial cells but also, healthy-appearing tubules near cysts. In the majority of mice, these changes preceded a rapid and massive onset of severe PKD that was remarkably similar to human ADPKD. Our data suggest that initial cysts are the principal trigger for a snowball effect driving the formation of new cysts, leading to the progression of severe PKD. In addition, this approach is a suitable model for mimicking human ADPKD and can be used for preclinical testing.

Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

“…Several studies have reported that many promising drugs showed potential therapeutic effects for ADP-KD in a large number of preclinical and clinical trials (1,7,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). However, some of those in clinical trials -these promising drugs included mTOR inhibitors (55,56), somatostatin analogs (57,58), ACEI/ ARB (59,60), and tyrosine kinase inhibitor (61) -did not prevent the decline of EGFR in ADPKD patients.…”

Rapamycin treatment dose‐dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell‐cycle‐associated CDK1/cyclin axis

“…Although preclinical studies have reported that rapamycin is an effective treatment for ADPKD in animal models , clinical trials of rapamycin treatment for ADPKD patients have been less successful . These poor clinical results might be due to insufficient rapamycin . To verify this possibility in a cohort study in vivo , we treated Vil ‐Cre; Pkd2 f3/f3 mice using three additional rapamycin protocols (Fig.…”

Emerging Therapies for Childhood Polycystic Kidney Disease

“…Although this may explain some of the focal nature of cyst formation in ADPKD, other factors have been shown to influence disease progression and severity. On a cellular level, these include: the developmental timing of PKD1 inactivation (45, 46); reduction in functional PC1 dosage (38, 47, 48); differences in sensitivity to PC1 dosage (48); and the proximity effect, where a cystic cell or nephron creates a “snowball effect” triggering cyst development in neighboring cells or nephrons (49). …”