TY - JOUR
T1 - Kidney-targeted inhibition of protein kinase C-α ameliorates nephrotoxic nephritis with restoration of mitochondrial dysfunction
AU - Kvirkvelia, Nino
AU - McMenamin, Malgorzata
AU - Warren, Marie
AU - Jadeja, Ravirajsinh N.
AU - Kodeboyina, Sai Karthik
AU - Sharma, Ashok
AU - Zhi, Wenbo
AU - O'Connor, Paul M.
AU - Raju, Raghavan
AU - Lucas, Rudolf
AU - Madaio, Michael P.
N1 - Funding Information:
We thank Drs. D. Eaton and E. Inscho for helpful discussions. This work was supported by National Institutes of Health grants R01 DK100564 (to RL, MPM) and R01 GM 101927 and RO1 GM122059 (to RR).
Publisher Copyright:
© 2018 International Society of Nephrology
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - PKC-α inhibition
KW - glomerular endothelial cells
KW - mitochondrial dysfunction
KW - nephritis
KW - proteomics
KW - targeted delivery
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U2 - 10.1016/j.kint.2018.01.032
DO - 10.1016/j.kint.2018.01.032
M3 - Article
C2 - 29731111
AN - SCOPUS:85046677929
SN - 0085-2538
VL - 94
SP - 280
EP - 291
JO - Kidney International
JF - Kidney International
IS - 2
ER -