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Kidney Week

Abstract: FR-PO986

Pkd1-Pkhd1 Interaction During Embryonic Development via a Mitochondria-Dependent Mechanism

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Walker, Rebecca V., umaryland, Baltimore, Maryland, United States
  • Yao, Qin None, umaryland, Baltimore, Maryland, United States
  • Xu, Hangxue, umaryland, Baltimore, Maryland, United States
  • Swaney, Kristen F., Johns Hopkins University, Baltimore, Maryland, United States
  • Li, Rong, Johns Hopkins University SOM, Baltimore, Maryland, United States
  • Outeda, Patricia, University of Maryland, Baltimore, Maryland, United States
  • Watnick, Terry J., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Germino, Gregory G., Deputy Director, NIDDK/NIH, Bethesda, Maryland, United States
  • Qian, Feng, University of Maryland School of Medicine, Baltimore, Maryland, United States

Group or Team Name

  • Qian

PKD occurs in autosomal dominant or recessive forms, caused by mutations mainly in PKD1 (PC1) or PKHD1 (FC) respectively. PC1 cleavage at the GPS motif is required for efficient ciliary trafficking and is frequently disrupted by PKD1 mutations. Non-cleavable PC1 in Pkd1V/V knockin mice sufficiently maintains kidney structure during embryonic development, yet rapid cystogenesis in distal tubules (DTs), but not proximal tubules (PTs), ensues postnatally. The pancreas remains intact throughout the lifespan. Pkhd1 mutants display negligible renal and pancreatic disease but show increased dilation in the renal DTs and pancreas in adult stages with heterozygous Pkd1 deletion; yet early-onset cystogenesis was not detected.


We performed genetic studies using Pkd1V and Pkhd1 mutant alleles to test for their interaction during development and the role of PC1 cleavage. To examine the role of Pkhd1 in the interaction, we analyzed biochemical, morphological and subcellular characteristics of mutant kidneys by western blot, scanning electron and immunofluorescent microscopy.


When combined with Pkhd1 hypomorphic or null mutation, Pkd1V/V mice developed rapid renal cystic dilation, progressing from PTs to DTs, during embryonic development and die perinatally. Pancreas is also severely dilated with a single central lumen. Mitochondrial structural defects were observed in Pkhd1 mutant kidneys. A FC C-terminal fragment translocated into mitochondria in cultured renal epithelial cells. Deleting this FC region caused PT cystic dilation and enhanced DT dilation in early postnatal Pkd1V/V mice.


Pkhd1 inactivation triggers severe early-onset renal and pancreatic cystogenesis in the absence of PC1 cleavage. Pkd1 and Pkhd1 interact for regulating proper tubular structure of the two major organs during embryonic development. This interaction operates for uncleaved PC1 at a non-ciliary site and involves FC’s C-terminus. Pkhd1 mutation may confer a strong procystic state that significantly contributes to early-onset kidney and pancreas disease through its C-terminus by a mitochondria-dependent mechanism.


  • NIDDK Support