Kidney-targeted inhibition of protein kinase C-α ameliorates nephrotoxic nephritis with restoration of mitochondrial dysfunction

Nino Kvirkvelia, Malgorzata McMenamin, Marie Warren, Ravirajsinh N. Jadeja, Sai Karthik Kodeboyina, Ashok Sharma, Wenbo Zhi, Paul M. O'Connor, Raghavan Raju, Rudolf Lucas, Michael P. Madaio

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

To investigate the role of protein kinase C-α (PKC-α) in glomerulonephritis, the capacity of PKC-α inhibition to reverse the course of established nephrotoxic nephritis (NTN) was evaluated. Nephritis was induced by a single injection of nephrotoxic serum and after its onset, a PKC-α inhibitor was administered either systemically or by targeted glomerular delivery. By day seven, all mice with NTN had severe nephritis, whereas mice that received PKC-α inhibitors in either form had minimal evidence of disease. To further understand the underlying mechanism, label-free shotgun proteomic analysis of the kidney cortexes were performed, using quantitative mass spectrometry. Ingenuity pathway analysis revealed 157 differentially expressed proteins and mitochondrial dysfunction as the most modulated pathway. Functional protein groups most affected by NTN were mitochondrial proteins associated with respiratory processes. These proteins were down-regulated in the mice with NTN, while their expression was restored with PKC-α inhibition. This suggests a role for proteins that regulate oxidative phosphorylation in recovery. In cultured glomerular endothelial cells, nephrotoxic serum caused a decrease in mitochondrial respiration and membrane potential, mitochondrial morphologic changes and an increase in glycolytic lactic acid production; all normalized by PKC-α inhibition. Thus, PKC-α has a critical role in NTN progression, and the results implicate mitochondrial processes through restoring oxidative phosphorylation, as an essential mechanism underlying recovery. Importantly, our study provides additional support for targeted therapy to glomeruli to reverse the course of progressive disease.

Original languageEnglish (US)
Pages (from-to)280-291
Number of pages12
JournalKidney International
Volume94
Issue number2
DOIs
StatePublished - Aug 2018

Keywords

  • PKC-α inhibition
  • glomerular endothelial cells
  • mitochondrial dysfunction
  • nephritis
  • proteomics
  • targeted delivery

ASJC Scopus subject areas

  • Nephrology

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