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Kidney Week

Abstract: SA-OR090

Inhibition of Drp1, the Master Regulator of Mitochondrial Fission, Ameliorates Polycystic Kidney Disease Progression

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Cassina, Laura, San Raffaele Scientific Institute, Milan, Italy
  • Chiaravalli, Marco, San Raffaele Scientific Institute, Milan, Italy
  • Boletta, Alessandra, San Raffaele Scientific Institute, Milan, Italy

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by mutations in PKD1 gene. We reported the remodeling of glucose utilization for energy production and a wide metabolic rewiring in mouse Pkd1 mutant cells and kidneys (Rowe 2013, Podrini 2018). Alterations in mitochondrial structure and mitochondrial respiration have also been described (Ishimoto 2017, Podrini 2018, Lin 2018). We investigated mitochondrial morphology and function in a PKD mouse model to elucidate their possible contribution to disease progression.


We analyzed mitochondria structure by transmission electron microscopy (TEM) and respiratory complexes by in situ activity staining on kidney sections from control and Ksp-Cre;Pkd1fl/- mice. Control and cystic mice were treated with daily intra-peritoneal injection of vehicle or Mdivi-1 (25mg/kg) from P6 to P8.


We measured the number of mitochondria, their size and shape in epithelial cells of cystic kidneys from Ksp-Cre;Pkd1fl/- mouse model at P4 by TEM and, in line with previous reports, we detected a decrease in the mitochondrial mass and aberrant mitochondria in cystic kidneys in comparison to controls. Inactivation of Pkd1 results also in the decreased activity of mitochondrial respiratory chain complexes cytochrome c oxidase and succinate dehydrogenase in DBA-positive cystic epithelia. Most mitochondria are in a round shape indicating fragmentation of the network in the epithelial cells of the cystic kidneys. We measured the amount of mitochondrial fusion/fission proteins by western blot and immunofluorescence and we found increased pro-fission Drp1 and decreased pro-fusion Opa1 and Mfn1 proteins in Ksp-Cre;Pkd1fl/- kidneys. In line with this, treatment with the Drp1-specific inhibitor Mdivi-1 reduces the cystic phenotype and the kidney to body weight ratio (vehicle, n=8, 7,28 ± 0,83%; Mdivi-1, n=9, 6,48 ± 0,64%, p<0,05), with amelioration of kidney function (BUN, vehicle, 233,3 ± 58,58 mg/dl; Mdivi-1, 187,9 ± 36,43 mg/dl, p<0,05).


Our data indicate that deletion of polycystin 1 in the kidney epithelium results in a reduction of mitochondrial respiration and increased mitochondrial fragmentation. Inhibition of the last ameliorates the PKD phenotype, indicating that mitochondrial fragmentation is a modifier of PKD progression.


  • Private Foundation Support