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4-PBA rescues hyperoxaluria induced nephrolithiasis by modulating urinary glycoproteins: Cross talk between

Rishi Bhardwaj1, Ankita Bhardwaj1, Devinder K Dhawan1

  • 1Department of Biophysics, Panjab University, Chandigarh, India.

Life Sciences
|July 9, 2022
PubMed
Abstract

Insights

The study shows that 4-PBA treatment improved kidney function in hyperoxaluric rats by reducing Endoplasmic Reticulum (ER) stress and restoring urinary glycoproteins and calcium homeostasis.

Area of Science:

  • Nephrology
  • Biochemistry
  • Cell Biology

Background:

  • Urinary glycoproteins like Tamm Horsfall Protein (THP) and Osteopontin (OPN) are key in kidney stone formation.
  • Endoplasmic Reticulum (ER) stress and mitochondria play crucial roles in nephrolithiasis.
  • The interplay between ER stress, urinary glycoproteins, and calcium homeostasis in hyperoxaluric conditions requires further elucidation.

Purpose of the Study:

  • To investigate the effect of 4-PBA, an ER stress mitigator, on urinary glycoproteins and calnexin (chaperone) in hyperoxaluric rats.
  • To explore the influence of 4-PBA on calcium homeostasis and ER-mitochondrial linkage in the context of nephrolithiasis.
  • To establish a connection between ER stress, urinary glycoprotein levels, and calcium balance in hyperoxaluric kidney disease.

Main Methods:

  • Hyperoxaluric rats were treated with 4-PBA for 9 days.
  • Renal tissues were analyzed for urinary glycoproteins (THP, OPN), calnexin, calcium homeostasis markers (SERCA activity, intracellular calcium), ER stress markers, protein folding/aggregation/degradation pathways (Congo Red assay), and mitochondrial linkage proteins (VDAC1, GRP75).
  • Redox status and ER environment were also assessed.

Main Results:

  • 4-PBA treatment normalized altered levels of THP, OPN, and calnexin.
  • Disrupted calcium homeostasis, evidenced by altered SERCA activity and intracellular calcium, was significantly improved.
  • 4-PBA intervention ameliorated ER stress markers, improved protein folding/aggregation/degradation, and restored redox status, establishing a link between ER stress and mitochondria (VDAC1, GRP75).

Conclusions:

  • 4-PBA treatment effectively mitigated ER-mitochondrial distress in hyperoxaluric rats, restoring protein homeostasis and calcium balance.
  • The findings highlight the critical role of ER stress and glycoproteins in hyperoxaluria.
  • A holistic approach focusing on glycoproteins and the ER environment is recommended for managing hyperoxaluria.
Keywords:
4-PBACalcium homeostasisCalnexinER environmentUrinary glycoproteins

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