Mitochondrial Metabolic Dysregulation and Structural Abnormalities in a Rat Model of Polycystic Kidney Disease
Authors: Irazabal Maria V , Arroyo Jennifer , Vuckovic Ivan , Zhang Song , Dzeja Petras , Macura Slobodan , Harris Peter , Torres Vicente 
Published: November 2023

BackgroundAutosomal Dominant Polycystic Kidney Disease (PKD) is the most frequent hereditary renal disease and the fourth leading cause of end‐stage renal disease. However, the exact mechanisms of cystogenesis and disease progression remain to be elucidated. Recent evidence suggests that a metabolic reprograming may underlie the dysregulation of several signaling pathways known to be affected in PKD. To identify the metabolic pathways associated with cystogenesis in the PKD kidney, we characterized the urinary, plasma, and tissue metabolome of PCK (a well established model of PKD) compared to Sprague‐Dawley (SD) wild‐type rats.MethodsMale and female PCK and SD rats were treated with dDAVP (PCK‐D, n=16 or SD‐D, n=12) to aggravate the cystic phenotype and achieve animals with different degrees of disease severity for a given age, or saline solution (PCK‐S, n=16 or SD‐S, n=12) as controls. Total kidney volume (TKV) gold standard to assess disease severity, were measured by MRI, and urinary, plasma, and tissue metabolites by proton nuclear magnetic resonance, 1H‐NMR. Kidney metabolites identified from renal tissues collected at euthanasia were correlated with TKV. Mitochondrial structure was assessed by electron microscopy in proximal tubules (PT), medullary thick ascending limb (mTAL), distal tubules (DT), and collecting ducts (CD).ResultsConsistent with previously published data, administration of dDAVP significantly aggravated the disease in PCK rats (TKV) without inducing a cystic phenotype in SD rats (Fig 1A–B). Analysis of PCK and SD metabolomes by Partial least squares‐discriminant analysis (PLS‐DA) score plots showed a significant separation between the groups (Fig 2). Integration of tissue, urine and plasma analysis revealed 5 metabolites (α‐ketoglutarate, fumarate, malate, citrate, and hippurate) consistently differentially expressed, among which 4 participate in the mitochondrial tricarboxylic acid (TCA) cycle (Fig 3). Moreover, tissue TCA cycle metabolites correlated directly with TKV (Fig 4). Mitochondrial area and matrix density were preserved in PT, mTAL, and DT of PCK rats, yet disruption of cristae membranes, swelling, and decreased matrix density were observed in their CD cystic cells (Fig 5).ConclusionsComprehensive multilevel metabolomics analysis showed significant dysregulations of several mitochondrial TCA cycle metabolites in PCK rats, which further aggravated with the more severe phenotype. Notably, these changes were associated with mitochondrial structural abnormalities in the CD. Our observations suggest that mitochondrial damage and metabolic dysregulations may be implicated in cystogenesis, and position mitochondria as important therapeutic targets in PKD.Support or Funding InformationThis study was supported by the Mayo Translational Polycystic Kidney Disease Center (NIDDK P30 DK090728) and an endowment from Robert M. and Billie J. Pirnie for Kidney Research