Bienholz 2011 Abstract IOC65
|Bienholz AH, Feldkamp T, Weinberg JM (2011) Role of Nonesterified Fatty Acids in Respiratory Impariment and Mitochondrial Deenergization of Proximal Renal Tubules Secondary to Hypoxia/Reoxygenation. MiPNet16.03.|
BACKGROUND: Hypoxia/reoxygenation (H/R) of proximal tubules leads to persistent ATP depletion due to decreased mitochondrial membrane potential (MMP) resulting from nonesterified fatty acid (NEFA)-mediated uncoupling that is paradoxically accompanied by respiratory inhibition rather than the stimulation expected for uncoupled states. METHODS: Since NEFA have been reported to directly inhibit electron transport in some settings we assessed respiratory function in isolated, permeabilized rabbit tubules after H/R as a function of NEFA availability. RESULTS: Compared to respiration supported by the complex II-dependent substrate, succinate, which was highly uncoupled after H/R but relatively well preserved (ADP-stimulated respiration (S3) of permeabilized tubules 71.0±8.5% of normoxic control (NC)), respiration supported by complex I-dependent substrates that normally predominate in cells was also uncoupled, but S3 was reduced to 26.9±3.3% of NC, P < 0.001 vs. succinate, N=5. With complex I substrates, acutely lowering NEFA after permeabilization improved coupling but only minimally increased S3. In contrast, lowering NEFA during 60 min. of reoxygenation prior to permeabilization increased S3 supported by complex I substrates, but it remained lower (55.7±7.5% of NC) than with succinate after the same treatment, 80.0±4.8%, p < 0.02. MMP at the end of H/R was much lower with complex I substrates (30.7±9.2% NC) than with succinate (67.4±4.5%), P < 0.004. Lowering NEFA during 60 min. of reoxygenation strongly improved recovery and decreased the MMP difference between complex I substrates (73.3±5.1% of NC) and succinate (83.4±6.6%). CONCLUSION: The studies indicate that selectively impaired utilization of complex I substrates to support respiration after H/R promotes NEFA-induced deenergization and is only minimally improved by acutely removing NEFA. In the presence of NEFA, the higher efficiency of complex I substrates to support electron transport does not mitigate the impact of the impaired respiration on MMP. However, lowering NEFA within cells for 60 min. allows strong recovery of MMP despite persistence of some respiratory impairment.
• Keywords: Acute Kidney Injury, Hypoxia/Reoxygenation, Isolated Permeabilized Renal Tubules, Respiration, Mitochondrial Membran Potential
• O2k-Network Lab: DE Essen Bienholz A
Authors: Bienholz AH (1,2), Feldkamp T (2) and Weinberg JM (1)
Affiliations: (1) Division of Internal Medicine, Department of Nephrology, University of Michigan, Ann Arbor, MI, USA. (2) Department of Nephrology, University of Essen, Essen, Germany.
References: 1. Weinberg JM, Roeser NF, Davis JA, Venkatachalam MA (1997). Glycine-protected, hypoxic, proximal tubules develop severely compromised energetic function. Kidney Int 52(1): 140-151. 2. Feldkamp T, Kribben A, Roeser NF, Senter RA, Weinberg JM (2006). Accumulation of nonesterified fatty acids causes the sustained energetic deficit in kidney proximal tubules after hypoxia-reoxygenation. Am J Physiol Renal Physiol 290(2): F465-477. 3. Feldkamp T, Weinberg JM, Hörbelt M, Von Kropff C, Witzke O, Nürnberger J, Kribben A (2009). Evidence of involvement of nonesterified fatty acid-induced protonophoric uncoupling during mitochondrial dysfunction caused by hypoxia and reoxygenation. Nephrol Dial Transplant 24(1): 43-51. 4. Data was presented in a poster at ASN Kidney Week 2011, Philadelphia, USA.