Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys

Abstract

Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.

Embryonic and foetal expression patterns of the ciliopathy gene CEP164

“…Together this suggests that CEP164 may have roles in both normal renal development and maintenance of kidney function in the human and mouse. Aberrant CEP164 activity in the kidney could contribute to abnormal primary ciliary function, causing dysregulation of cell division and cell signalling, leading to cystogenesis, which has been suggested in a recent study using murine Cep164 collecting duct cell knockdown [61]. This is consistent with the NPHP-RC phenotype present in most patients with CEP164 mutations [1].…”

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

“…In addition, treatment with the mTOR inhibitor rapamycin reduced Cdk1 and Cdk2 activity and attenuated the cystic phenotype, suggesting that the effect of mTOR inhibition is partly mediated by CDK inhibition ( Zhang et al, 2020 ). Finally, roscovitine was demonstrated to attenuate renal cyst progression in a kidney-specific Cep164 -knockout mouse model characterized by rapidly progressive cystic kidney enlargement ( Airik et al, 2019 ). In summary, studies performed mostly in models of infantile NPH have demonstrated that targeting cell cycle dysregulation and proliferation using CDK inhibitors is an efficient approach to limit cyst growth.…”

The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis

“…At least six proteins are required for the establishment of the distal appendages ensemble: centrosomal protein 83 (CEP83), centrosomal protein 164 (CEP164), centrosomal protein 89 (CEP89), sodium channel and clathrin linker 1 (SCLT1), Fas binding factor 1 (FBF1), and leucine rich repeat containing 45 (LRRC45) [15,18]. The disruption of the DAP complex results in an impaired ciliary assembly and mutations in genes encoding DAP proteins are characterized by phenotypes affecting various organs associated with ciliopathies [36][37][38][39][40][41].…”

“…Global Cep164 deficiency in mice leads to early embryonic lethality due to holoprosencephaly, cardiac looping defects, and a truncated posterior trunk [106]. A collecting duct-specific deletion of Cep164 abolishes ciliogenesis and leads to a dysregulated cell cycle and epithelia cell hyperproliferation that drives renal cyst growth [40]. Interestingly, treatment of these mutant mice with a cyclin-dependent kinase inhibitor reduces cortical cyst formation and epithelial proliferation, restoring normal cortical histology [40].…”

“…A collecting duct-specific deletion of Cep164 abolishes ciliogenesis and leads to a dysregulated cell cycle and epithelia cell hyperproliferation that drives renal cyst growth [40]. Interestingly, treatment of these mutant mice with a cyclin-dependent kinase inhibitor reduces cortical cyst formation and epithelial proliferation, restoring normal cortical histology [40]. Depletion of Cep164 in multiciliated cells of FOXJ1-positive tissues results in hydrocephalus and perturbs the differentiation of multiciliated cells in murine airway and oviduct epithelia [106].…”