Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension

Abstract

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (Po2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney Qo2, cortical Po2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 ± 3.3 vs. 0.9 ± 0.4 pmol O2 · s(-1)· mg protein(-1), P < 0.05) and increased whole kidney Qo2 (55 ± 16 vs. 33 ± 10 μmol O2/min, P < 0.05). Corticomedullary Po2 was lower in TX compared with 1K-CON (30 ± 13 vs. 47 ± 4 μM, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Qo2, Po2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage.

Innovative Perspective: Gadolinium-Free Magnetic Resonance Imaging in Long-Term Follow-Up after Kidney Transplantation

“…Indeed it was demonstrated in experimental diabetes that hypoxia had occurred at an early stage (dos Santos et al, 2007) before any histologic damage could be observed (Manotham et al, 2004). This has also been observed in experimental kidney transplantation (Papazova et al, 2015). Moreover, hypoxia-inducible factor-1alpha has been immunohistochemically detected in kidney allografts with (sub)clinical rejection at 3 months after transplantation and beyond (Rosenberger et al, 2007).…”

Exogenous and endogenous angiotensin‐II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow

“…Renal oxygen delivery () was calculated as the product of RBF and arterial O 2 ct, while renal oxygen consumption () was calculated as the product of RBF and the difference between arterial and renal venous blood oxygen content (Papazova et al . ).…”

ERK and p38 upregulation versus Bcl-6 downregulation in rat kidney epithelial cells exposed to prolonged hypoxia

“…In kidney transplantation, hypoxia is a critical factor affecting the development of renal damage during the transplant process from donor to recipient. 8,12 Hypoxia is also believed to play a key role in both acute and chronic kidney diseases and in the transition from acute to chronic kidney diseases. 38 In fact, it is thought that hypoxia plays a major Relative quantitation of phosphorylated ERK1/2 (P-ERK1/2)/total ERK1/2 (T-ERK1/2).…”

“…7 Hypoxia is also an acknowledged pathway to renal injury and ischemiareperfusion, which is an inevitable event accompanying renal transplantation and is considered a common cause for delayed graft function and acute renal failure. [8][9][10][11] Understanding the mechanisms involved in hypoxic pathophysiology is of great importance for the prevention and treatment of hypoxic renal injury, especially for improving renal allograft outcome in the recipient after kidney transplantation. 12 Hypoxia can activate a large range of signaling networks and regulate the expression of a variety of growth factors, cytokines, and signaling molecules in a cell-and tissue-specific manner.…”