Dose-dependent regulation of kidney mitochondrial function by angiotensin II
Keywords:
angiotensin II, mitochondria function, mitochondria leak respiration, uncoupling, kidney, renin-angiotensin II-aldosterone system
Abstract
Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration.
Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury.
Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased.
Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.
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References
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14. Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. 2008;102:488–96. doi: 10.1161/CIRCRESAHA.107.162800
15. Yan P, Chen K, Wang Q, Yang D, Li D, Yang Y. UCP-2 is involved in angiotensin-II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice. PLoS One. 2017;12:e0179743. doi: 10.1371/journal.pone.0179743
16. Sabaa N, Miroux B, Coffman, Mc T, Collins S, Ricquier D, Dussaule J-C, et al. UCP-2 does not modulate angiotensin II-induced high blood pressure but limits the development of hypertensive renal sclerosis. J Hypertens. 2005;23:A11. doi: 10.1097/01.hjh.0000177375.70196.08
17. Friederich-Persson M, Persson P. Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats. Am J Physiol Renal Physiol. 2020;318:F683–8. doi: 10.1152/ajprenal.00417.2019
18. Benbadis SR. Neglecting epileptic syndromes. J Clin Neurophysiol. 1996;13:458. doi: 10.1097/00004691-199609000-00094
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21. Friederich-Persson M, Persson P, Fasching A, Hansell P, Nordquist L, Palm F. Increased kidney metabolism as a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats. Adv Exp Med Biol. 2013;789:9–14. doi: 10.1007/978-1-4614-7411-1_2
22. Sivertsson E, Friederich-Persson M, Persson P, Nangaku M, Hansell P, Palm F. Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease. PLoS One. 2022;17:e0264524. doi: 10.1371/journal.pone.0264524
23. Edlund J, Hansell P, Fasching A, Liss P, Weis J, Glickson JD, et al. Reduced oxygenation in diabetic rat kidneys measured by T2* weighted magnetic resonance micro-imaging. Adv Exp Med Biol. 2009;645:199–204. doi: 10.1007/978-0-387-85998-9_31
24. Palm F, Ortsäter H, Hansell P, Liss P, Carlsson PO. Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model. Diabetes Metab Res Rev. 2004;20:452–9. doi: 10.1002/dmrr.472
25. Rosenberger C, Khamaisi M, Abassi Z, Shilo V, Weksler-Zangen S, Goldfarb M, et al. Adaptation to hypoxia in the diabetic rat kidney. Kidney Int. 2008;73:34–42. doi: 10.1038/sj.ki.5002567
26. Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia. 2003;46:1153–60. doi: 10.1007/s00125-003-1155-z
27. Palm F, Friederich M, Carlsson PO, Hansell P, Teerlink T, Liss P. Reduced nitric oxide in diabetic kidneys due to increased hepatic arginine metabolism: implications for renomedullary oxygen availability. Am J Physiol Renal Physiol. 2008;294:F30–7. doi: 10.1152/ajprenal.00166.2007
28. Persson MF, Welch WJ, Wilcox CS, Palm F. Kidney function after in vivo gene silencing of uncoupling protein-2 in streptozotocin-induced diabetic rats. Adv Exp Med Biol. 2013;765:217–23. doi: 10.1007/978-1-4614-4989-8_30
29. Ries M, Basseau F, Tyndal B, Jones R, Deminiere C, Catargi B, et al. Renal diffusion and BOLD MRI in experimental diabetic nephropathy. Blood oxygen level-dependent. J Magn Reson Imaging. 2003;17:104–13. doi: 10.1002/jmri.10224
30. Franzén S, Pihl L, Khan N, Gustafsson H, Palm F. Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice. Am J Physiol Renal Physiol. 2016;310:F807–9. doi: 10.1152/ajprenal.00049.2016
31. Welch WJ, Baumgärtl H, Lübbers D, Wilcox CS. Nephron pO2 and renal oxygen usage in the hypertensive rat kidney. Kidney Int. 2001;59:230–7. doi: 10.1046/j.1523-1755.2001.00483.x
32. Welch WJ, Blau J, Xie H, Chabrashvili T, Wilcox CS. Angiotensin-induced defects in renal oxygenation: role of oxidative stress. Am J Physiol Heart Circ Physiol. 2005;288:H22–8. doi: 10.1152/ajpheart.00626.2004
33. Manotham K, Tanaka T, Matsumoto M, Ohse T, Miyata T, Inagi R, et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc Nephrol. 2004;15:1277–88. doi: 10.1097/01.ASN.0000125614.35046.10
34. Yin WJ, Liu F, Li XM, Yang L, Zhao S, Huang ZX, et al. Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI. Eur J Radiol 2012;81:1426–31. doi: 10.1016/j.ejrad.2011.03.045
35. Inoue T, Kozawa E, Okada H, Inukai K, Watanabe S, Kikuta T, et al. Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J Am Soc Nephrol. 2011;22:1429–34. doi: 10.1681/ASN.2010111143
36. Li G, Wang M, Hao L, Loo WT, Jin L, Cheung MN, et al. Angiotensin II induces mitochondrial dysfunction and promotes apoptosis via JNK signalling pathway in primary mouse calvaria osteoblast. Arch Oral Biol. 2014;59:513–23. doi: 10.1016/j.archoralbio.2014.02.015
37. Echtay KS, Murphy MP, Smith RA, Talbot DA, Brand MD.Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem. 2002;277:47129–35. doi: 10.1074/jbc.M208262200
38. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, et al. Superoxide activates mitochondrial uncoupling proteins. Nature. 2002;415:96–9. doi: 10.1038/415096a
39. de Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, Inserra F. Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1616–25. doi: 10.1152/ajpregu.00615.2005
40. Dynnik VV, Grishina EV, Fedotcheva NI. The mitochondrial NO-synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore. FEBS J. 2020;287:1525–36. doi: 10.1111/febs.15090
41. Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK. p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem. 1996;271:23317–21. doi: 10.1074/jbc.271.38.23317
42. Franzén S, Friederich-Persson M, Fasching A, Hansell P, Nangaku M, Palm F. Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes. Am J Physiol Renal Physiol. 2014;306:F1171–8. doi: 10.1152/ajprenal.00595.2013
2. Foundation NK. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850–86. doi: 10.1053/j.ajkd.2012.07.005
3. Fine LG, Bandyopadhay D, Norman JT. Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int Suppl. 2000;75:S22–6. doi: 10.1046/j.1523-1755.57.s75.12.x
4. Fine LG, Orphanides C, Norman JT. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl. 1998;65:S74–8.
5. Hansell P, Welch WJ, Blantz RC, Palm F. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol. 2013;40:123–37. doi: 10.1111/1440-1681.12034
6. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17:17–25. doi: 10.1681/ASN.2005070757
7. Friederich M, Nordquist L, Olerud J, Johansson M, Hansell P, Palm F. Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney. Adv Exp Med Biol. 2009;645:205–12. doi: 10.1007/978-0-387-85998-9_32
8. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004;37:755–67. doi: 10.1016/j.freeradbiomed.2004.05.034
9. Sivertsson E, Friederich-Persson M, Öberg CM, Fasching A, Hansell P, Rippe B, et al. Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability. Am J Physiol Renal Physiol. 2018;314:F864–72. doi: 10.1152/ajprenal.00033.2017
10. Friederich M, Fasching A, Hansell P, Nordquist L, Palm F. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 2008;1777:935–40. doi: 10.1016/j.bbabio.2008.03.030
11. Friederich-Persson M, Persson P, Hansell P, Palm F. Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes. Acta Physiol (Oxf). 2018;223:e13058. doi: 10.1111/apha.13058
12. Friederich-Persson M, Aslam S, Nordquist L, Welch WJ, Wilcox CS, Palm F. Acute knockdown of uncoupling protein-2 increases uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys. PLoS One. 2012;7:e39635. doi: 10.1371/journal.pone.0039635
13. Schiffer TA, Löf L, Gallini R, Kamali-Moghaddam M, Carlström M, Palm F. Mitochondrial respiration-dependent ANT2-UCP2 interaction. Front Physiol. 2022;13:866590. doi: 10.3389/fphys.2022.866590
14. Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. 2008;102:488–96. doi: 10.1161/CIRCRESAHA.107.162800
15. Yan P, Chen K, Wang Q, Yang D, Li D, Yang Y. UCP-2 is involved in angiotensin-II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice. PLoS One. 2017;12:e0179743. doi: 10.1371/journal.pone.0179743
16. Sabaa N, Miroux B, Coffman, Mc T, Collins S, Ricquier D, Dussaule J-C, et al. UCP-2 does not modulate angiotensin II-induced high blood pressure but limits the development of hypertensive renal sclerosis. J Hypertens. 2005;23:A11. doi: 10.1097/01.hjh.0000177375.70196.08
17. Friederich-Persson M, Persson P. Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats. Am J Physiol Renal Physiol. 2020;318:F683–8. doi: 10.1152/ajprenal.00417.2019
18. Benbadis SR. Neglecting epileptic syndromes. J Clin Neurophysiol. 1996;13:458. doi: 10.1097/00004691-199609000-00094
19. Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, et al. Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A. 2011;108:14849–54. doi: 10.1073/pnas.1101507108
20. Kawada N, Imai E, Karber A, Welch WJ, Wilcox CS. A mouse model of angiotensin II slow pressor response: role of oxidative stress. J Am Soc Nephrol. 2002;13:2860–8. doi: 10.1097/01.ASN.0000035087.11758.ED
21. Friederich-Persson M, Persson P, Fasching A, Hansell P, Nordquist L, Palm F. Increased kidney metabolism as a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats. Adv Exp Med Biol. 2013;789:9–14. doi: 10.1007/978-1-4614-7411-1_2
22. Sivertsson E, Friederich-Persson M, Persson P, Nangaku M, Hansell P, Palm F. Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease. PLoS One. 2022;17:e0264524. doi: 10.1371/journal.pone.0264524
23. Edlund J, Hansell P, Fasching A, Liss P, Weis J, Glickson JD, et al. Reduced oxygenation in diabetic rat kidneys measured by T2* weighted magnetic resonance micro-imaging. Adv Exp Med Biol. 2009;645:199–204. doi: 10.1007/978-0-387-85998-9_31
24. Palm F, Ortsäter H, Hansell P, Liss P, Carlsson PO. Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model. Diabetes Metab Res Rev. 2004;20:452–9. doi: 10.1002/dmrr.472
25. Rosenberger C, Khamaisi M, Abassi Z, Shilo V, Weksler-Zangen S, Goldfarb M, et al. Adaptation to hypoxia in the diabetic rat kidney. Kidney Int. 2008;73:34–42. doi: 10.1038/sj.ki.5002567
26. Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO. Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia. 2003;46:1153–60. doi: 10.1007/s00125-003-1155-z
27. Palm F, Friederich M, Carlsson PO, Hansell P, Teerlink T, Liss P. Reduced nitric oxide in diabetic kidneys due to increased hepatic arginine metabolism: implications for renomedullary oxygen availability. Am J Physiol Renal Physiol. 2008;294:F30–7. doi: 10.1152/ajprenal.00166.2007
28. Persson MF, Welch WJ, Wilcox CS, Palm F. Kidney function after in vivo gene silencing of uncoupling protein-2 in streptozotocin-induced diabetic rats. Adv Exp Med Biol. 2013;765:217–23. doi: 10.1007/978-1-4614-4989-8_30
29. Ries M, Basseau F, Tyndal B, Jones R, Deminiere C, Catargi B, et al. Renal diffusion and BOLD MRI in experimental diabetic nephropathy. Blood oxygen level-dependent. J Magn Reson Imaging. 2003;17:104–13. doi: 10.1002/jmri.10224
30. Franzén S, Pihl L, Khan N, Gustafsson H, Palm F. Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice. Am J Physiol Renal Physiol. 2016;310:F807–9. doi: 10.1152/ajprenal.00049.2016
31. Welch WJ, Baumgärtl H, Lübbers D, Wilcox CS. Nephron pO2 and renal oxygen usage in the hypertensive rat kidney. Kidney Int. 2001;59:230–7. doi: 10.1046/j.1523-1755.2001.00483.x
32. Welch WJ, Blau J, Xie H, Chabrashvili T, Wilcox CS. Angiotensin-induced defects in renal oxygenation: role of oxidative stress. Am J Physiol Heart Circ Physiol. 2005;288:H22–8. doi: 10.1152/ajpheart.00626.2004
33. Manotham K, Tanaka T, Matsumoto M, Ohse T, Miyata T, Inagi R, et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc Nephrol. 2004;15:1277–88. doi: 10.1097/01.ASN.0000125614.35046.10
34. Yin WJ, Liu F, Li XM, Yang L, Zhao S, Huang ZX, et al. Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI. Eur J Radiol 2012;81:1426–31. doi: 10.1016/j.ejrad.2011.03.045
35. Inoue T, Kozawa E, Okada H, Inukai K, Watanabe S, Kikuta T, et al. Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J Am Soc Nephrol. 2011;22:1429–34. doi: 10.1681/ASN.2010111143
36. Li G, Wang M, Hao L, Loo WT, Jin L, Cheung MN, et al. Angiotensin II induces mitochondrial dysfunction and promotes apoptosis via JNK signalling pathway in primary mouse calvaria osteoblast. Arch Oral Biol. 2014;59:513–23. doi: 10.1016/j.archoralbio.2014.02.015
37. Echtay KS, Murphy MP, Smith RA, Talbot DA, Brand MD.Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem. 2002;277:47129–35. doi: 10.1074/jbc.M208262200
38. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, et al. Superoxide activates mitochondrial uncoupling proteins. Nature. 2002;415:96–9. doi: 10.1038/415096a
39. de Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, Inserra F. Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1616–25. doi: 10.1152/ajpregu.00615.2005
40. Dynnik VV, Grishina EV, Fedotcheva NI. The mitochondrial NO-synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore. FEBS J. 2020;287:1525–36. doi: 10.1111/febs.15090
41. Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK. p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem. 1996;271:23317–21. doi: 10.1074/jbc.271.38.23317
42. Franzén S, Friederich-Persson M, Fasching A, Hansell P, Nangaku M, Palm F. Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes. Am J Physiol Renal Physiol. 2014;306:F1171–8. doi: 10.1152/ajprenal.00595.2013
Published
2023-12-21
How to Cite
Sivertsson E., Balboa A., Schiffer T. A., Hansell P., Friederich-Persson M., Persson P., & Palm F. (2023). Dose-dependent regulation of kidney mitochondrial function by angiotensin II. Upsala Journal of Medical Sciences, 128(1). https://doi.org/10.48101/ujms.v128.10312
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