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Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
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Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2

Khalil El Karoui1,2, Amandine Viau1, Olivier Dellis3

  • 1Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Descartes, Institut Necker Enfants Malades, Département « Croissance et Signalisation », Hôpital Necker Enfants Malades, 149 Rue de Sèvres, Paris 75015, France.

Nature Communications
|January 21, 2016
PubMed

Insights

4-phenylbutyric acid (PBA) offers a new therapeutic strategy for chronic kidney disease (CKD) by counteracting proteinuria's toxic effects. This approach reduces kidney damage and improves outcomes in proteinuric conditions.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Proteinuria in chronic kidney disease (CKD) causes severe tubulointerstitial damage, progressing to end-stage renal disease.
  • Albuminuria triggers cellular stress pathways in kidney tubules, contributing to disease progression.

Purpose of the Study:

  • To identify novel therapeutic strategies for proteinuria-induced kidney damage.
  • To investigate the role of Lipocalin 2 (LCN2) in CKD pathogenesis and explore 4-phenylbutyric acid (PBA) as a potential treatment.

Main Methods:

  • Investigated the mechanism of albumin-induced tubular injury, focusing on unfolded protein response (UPR) and apoptosis.
  • Utilized Lcn2 gene-inactivated and wild-type proteinuric mouse models.
  • Administered PBA to assess its protective effects on kidney morphology and function.

Main Results:

  • Albumin induces tubular UPR and apoptosis via cytosolic calcium increase and LCN2 modulation through ATF4.
  • Lcn2 deficiency ameliorates ER stress, tubulointerstitial lesions, and mortality in proteinuric mice.
  • PBA treatment protects kidneys from functional and morphological decline in proteinuric mice, with relevance to human CKD patients where LCN2 is elevated.

Conclusions:

  • Identified PBA as a novel therapeutic agent against proteinuria-induced CKD.
  • Demonstrated the critical role of the LCN2 pathway in CKD progression.
  • Proposed PBA as a strategy to enhance current treatments like RAS inhibitors for proteinuric CKD.

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