Mitochondrial impairment in the five-sixth nephrectomy model of chronic renal failure: proteomic approach

Kidney injuries provoke considerable adjustment of renal physiology, metabolism, and architecture to nephron loss. Despite remarkable regenerative capacity of the renal tissue, these adaptations often lead to tubular atrophy, interstial and glomerular scaring, and development of chronic kidney disease. The therapeutic strategies for prevention of the transition from acute kidney damage to a chronic condition are limited. The

The results of the study demonstrated that notable alterations in the renal cortex of 5/6 nephrectomized rats were associated with mitochondrial damage, however mitochondrial biogenesis and autophagy for replacement of damaged mitochondria were not stimulated. Accumulation of dysfunctional mitochondria after 5/6 nephrectomy may cause multiple adjustments in biosynthetic pathways, energy production, ROS signaling, and activation of pro-cell death regulatory pathways thus contributing to the development of chronic kidney disease.

Sprague-Dawley 5/6 nephrectomized rats and sham-operated controls were sacrificed at day 28 post-surgery. To identify proteins with notable alteration of expression we applied a 2D-proteomics approach followed by mass-spectrometry. Altered expression of identified and related proteins was validated by Western blotting and immunohistochemistry.

Proteins with increased levels of expression after partial nephrectomy were albumin and vimentin. Proteins with decreased expression were metabolic or mitochondrial. Western blotting analysis showed that the renal cortex of nephrectomized rats expressed decreased amount (by ~50%) of proteins from the inner mitochondrial compartment - the beta-oxidation enzyme MCAD, the structural protein GRP-75, and the oxidative phosphorylation protein COXIV. Mitochondrial DNA copy number was decreased by 30% in the cortex of PNx rats. In contrast, the levels of an outer mitochondrial membrane protein, VDAC1, remained unchanged in remnant kidneys. Mitochondrial biogenesis was not altered after renal mass ablation as was indicated by unchanged levels of PPARγ and PGC1α proteins. Autophagy related protein Beclin 1 was up-regulated in remnant kidneys, however the level of LC3-II protein was unchanged. BNIP3 protein, which can initiate both mitochondrial autophagy and cell death, was up-regulated considerably in kidneys of nephrecomized rats. Conclusions: The results of the study demonstrated that notable alterations in the renal cortex of 5/6 nephrectomized rats were associated with mitochondrial damage, however mitochondrial biogenesis and autophagy for replacement of damaged mitochondria were not stimulated. Accumulation of dysfunctional mitochondria after 5/6 nephrectomy may cause multiple adjustments in biosynthetic pathways, energy production, ROS signaling, and activation of pro-cell death regulatory pathways thus contributing to the development of chronic kidney disease.