4.8 Article

Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 9, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI147253

Keywords

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Funding

  1. Deutsche Forschungsgemeinschaft (DFG) [BE 3910/8-1, BE 3910/9-1, (SFB 1453)]
  2. Federal Ministry of Education and Research (BMBF) [01GM1903I, 01GM1903G]
  3. DFG [OK 1984/1-4]
  4. Bundesministerium fur Bildung und Forschung (BMBF) [STOP-FSGS-01GM1901C]
  5. Else-Kroner Fresenius Foundation (Else Kroner-Promotionskolleg -iPRIME)
  6. European Research Council (ERC) [616891]
  7. H2020-IMI2 consortium BEAt-DKD [115974]
  8. European Union
  9. European Federation of Pharmaceutical Industry and Associations (EFPIA)
  10. Juvenile Diabetes Research Foundation (JDRF)
  11. BMBF

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Impairment of the glomerular filtration barrier (GFB) can lead to glomerular diseases, and P3H2 protein may act as a regulator of GFB and play an important role in its function.
The glomerular filtration barrier (GFB) produces primary urine and is composed of a fenestrated endothelium, a glomerular basement membrane (GBM), podocytes, and a slit diaphragm. Impairment of the GFB leads to albuminuria and microhematuria. The GBM is generated via secreted proteins from both endothelial cells and podocytes and is supposed to majorly contribute to filtration selectivity. While genetic mutations or variations of GBM components have been recently proposed to be a common cause of glomerular diseases, pathways modifying and stabilizing the GBM remain incompletely understood. Here, we identified prolyl 3-hydroxylase 2 (P3H2) as a regulator of the GBM in an a cohort of patients with albuminuria. P3H2 hydroxylates the 3' of prolines in collagen IV subchains in the endoplasmic reticulum. Characterization of a P3h2(Delta Pod) mouse line revealed that the absence of P3H2 protein in podocytes induced a thin basement membrane nephropathy (TBMN) phenotype with a thinner GBM than that in WT mice and the development of microhematuria and microalbuminuria over time. Mechanistically, differential quantitative proteomics of the GBM identified a significant decrease in the abundance of collagen IV subchains and their interaction partners in P3h2(Delta Pod) mice. To our knowledge, P3H2 protein is the first identified GBM modifier, and loss or mutation of P3H2 causes TBMN and focal segmental glomerulosclerosis in mice and humans.

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