The role of diabetic nephropathy in the outcome of acute renal injury (AKI) is not well defined. Herein we evaluate the outcome of lipopolysaccharide- (LPS-) induced AKI in streptozotocin-induced diabetes, as well as the potential role of Hypoxia Inducible Factor (HIF-1α) in this condition. Although 6？h after LPS injection all mice developed a decrease in renal function, proteinuric diabetic mice showed a better recovery of this parameter throughout the study (72？h). Both HIF-1α and vascular endothelium growth factor (VEGF) were found to be upregulated in diabetic mice. After LPS injection, all animals showed an upregulation of these factors, although it was higher in the diabetic group. Glycated albumin (GA) was found to upregulate HIF-1α in HK-2 cells, which resulted in increased production of VEGF. Interestingly, LPS cooperated with GA to induce HIF-1α upregulation. In conclusion, diabetic mice display a better recovery of AKI after experimental endotoxemia. Moreover, these animals showed an increased expression of both HIF-1α and VEGF that was reproduced by incubating renal cells with GA. Since VEGF is considered a survival factor for tubular cells, our findings suggest that diabetes displays HIF-1α upregulation that might function as a “precondition state” offering protection from endotoxic AKI. 1. Introduction The role of diabetes in the outcome of acute renal injury (AKI) is not well understood and may depend upon the cause of the injury as well as on the stage of diabetic renal involvement. Among the various causes of AKI, endotoxemia, a major component of sepsis, remains an elusive and challenging condition which is still lacking treatment. Although it is known that rodents with experimental diabetes are protected from certain nephrotoxic agents [1–3], diabetes has been recognized as an independent risk factor for the development of AKI in a variety of clinical settings, including sepsis [4–8]. Hypoxia-inducible factor (HIF-1α) allows the adaptive response to hypoxia by stimulating the expression of target genes such as erythropoietin, enzymes involved in glucose metabolism, and the vascular endothelial growth factor A (VEGF-A) [9]. The later has been recognized as a survival factor for proximal tubular cells [10]. HIF-1α is a heterodimer transcription factor consisting of a constitutively expressed β subunit and two α subunits, HIF-1α or HIF-2α. In normoxia, HIF-1α is continuously synthesized but rapidly ubiquitinated and subsequently degraded by the cellular proteasome [11]. Under hypoxia, the HIF-1α ubiquitination is suppressed. HIF-1α
References
[1]
W. C. Elliott, D. C. Houghton, and D. N. Gilbert, “Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes,” Journal of Pharmacology and Experimental Therapeutics, vol. 233, no. 1, pp. 264–270, 1985.
[2]
K. Hamilton, E. J. Eaton, H. O. Garland, and S. Old, “Effect of experimental diabetes mellitus on gentamicin-induced acute renal functional changes in the anaesthetized rat,” Clinical and Experimental Pharmacology and Physiology, vol. 25, no. 3-4, pp. 231–235, 1998.
[3]
A. V. Dnyanmote, S. P. Sawant, E. A. Lock, J. R. Latendresse, A. A. Warbritton, and H. M. Mehendale, “Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair,” Toxicology and Applied Pharmacology, vol. 211, no. 2, pp. 133–147, 2006.
[4]
M. R. Rudnick, S. Goldfarb, L. Wexler et al., “Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial,” Kidney International, vol. 47, no. 1, pp. 254–261, 1995.
[5]
P. A. McCullough, R. Wolyn, L. L. Rocher, R. N. Levin, and W. W. O'Neill, “Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality,” American Journal of Medicine, vol. 103, no. 5, pp. 368–375, 1997.
[6]
C. V. Thakar, S. Arrigain, S. Worley, J.-P. Yared, and E. P. Paganini, “A clinical score to predict acute renal failure after cardiac surgery,” Journal of the American Society of Nephrology, vol. 16, no. 1, pp. 162–168, 2005.
[7]
M. H. Rosner and M. D. Okusa, “Acute kidney injury associated with cardiac surgery,” Clinical Journal of the American Society of Nephrology, vol. 1, no. 1, pp. 19–32, 2006.
[8]
M. D. Griffin, E. J. Bergstralh, and T. S. Larson, “Renal papillary necrosis a sixteen-year clinical experience,” Journal of the American Society of Nephrology, vol. 6, no. 2, pp. 248–256, 1995.
[9]
G. L. Semenza, “Signal transduction to hypoxia-inducible factor 1,” Biochemical Pharmacology, vol. 64, no. 5-6, pp. 993–998, 2002.
[10]
J. Kanellis, S. Fraser, M. Katerelos, and D. A. Power, “Vascular endothelial growth factor is a survival factor for renal tubular epithelial cells,” American Journal of Physiology, vol. 278, no. 6, pp. F905–F915, 2000.
[11]
P. Jaakkola, D. R. Mole, Y.-M. Tian et al., “Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation,” Science, vol. 292, no. 5516, pp. 468–472, 2001.
[12]
M. Ivan, K. Kondo, H. Yang et al., “HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing,” Science, vol. 292, no. 5516, pp. 464–468, 2001.
[13]
S. Kaluz, M. Kaluzová, and E. J. Stanbridge, “Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element,” Clinica Chimica Acta, vol. 395, no. 1-2, pp. 6–13, 2008.
[14]
J. Zhou and B. Brune, “Cytokines and hormones in the regulation of hypoxia inducible factor-1alpha (HIF-1alpha),” Cardiovascular & Hematological Agents in Medicinal Chemistry, vol. 4, no. 3, pp. 189–197, 2006.
[15]
I. R. Botusan, V. G. Sunkari, O. Savu et al., “Stabilization of HIF-1α is critical to improve wound healing in diabetic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 49, pp. 19426–19431, 2008.
[16]
M. Nangaku, R. Inagi, T. Miyata, and T. Fujita, “Hypoxia and hypoxia-inducible factor in renal disease,” Nephron, vol. 110, no. 1, article e1, 2008.
[17]
C. C. Tisher and T. H. Hostetter, “Diabetic nephropathy,” in Renal Pathology, C. C. Tisher and B. M. Brenner, Eds., vol. 2, JB Lippincott, Philadelphia, Pa, USA, 1994.
[18]
C. E. Guthrow, M. A. Morris, and J. F. Day, “Enhanced nonenzymatic glucosylation of human serum albumin in diabetes mellitus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 9, pp. 4258–4261, 1979.
[19]
A. Izquierdo, P. López-Luna, A. Ortega et al., “The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes,” Kidney International, vol. 69, no. 12, pp. 2171–2178, 2006.
[20]
A. B. Fernandez-Martinez, M. I. Jimenez, I. S. Hernandez, et al., “Mutual regulation of hypoxic and retinoic acid related signalling in tubular proximal cells,” International Journal of Biochemistry & Cell Biology, vol. 43, no. 8, pp. 1198–1207, 2011.
[21]
A. A. Sharfuddin and B. A. Molitoris, “Pathophysiology of ischemic acute kidney injury,” Nature Reviews Nephrology, vol. 7, no. 4, pp. 189–200, 2011.
[22]
C. Treins, S. Giorgetti-Peraldi, J. Murdaca, and E. Van Obberghen, “Regulation of vascular endothelial growth factor expression by advanced glycation end products,” Journal of Biological Chemistry, vol. 276, no. 47, pp. 43836–43841, 2001.
[23]
C. E. Guthrow, M. A. Morris, and J. F. Day, “Enhanced nonenzymatic glucosylation of human serum albumin in diabetes mellitus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 9, pp. 4258–4261, 1979.
[24]
M. P. Cohen and F. N. Ziyadeh, “Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 7, no. 2, pp. 183–190, 1996.
[25]
Y. Zhang, Y. Shi, Y. Liu et al., “Growth pattern switch of renal cells and expression of cell cycle related proteins at the early stage of diabetic nephropathy,” Biochemical and Biophysical Research Communications, vol. 363, no. 1, pp. 159–164, 2007.
[26]
S. V. Griffin and S. J. Shankland, “Renal hyperplasia and hypertrophy: role of cell cylce regulatory proteins,” in The Kidney Physiology and Pathophysiology, R. J. Alpern and S. C. Hebert, Eds., chapter 27, pp. 723–742, New York, NY, USA, 2008.
[27]
R. J. Baines and N. J. Brunskill, “Tubular toxicity of proteinuria,” Nature Reviews Nephrology, vol. 7, no. 3, pp. 177–180, 2011.
[28]
M. Thiel, C. C. Caldwell, S. Kreth et al., “Targeted deletion of HIF-1α gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival,” PLoS ONE, vol. 2, no. 9, article e853, 2007.
[29]
S. Ohtomo, M. Nangaku, Y. Izuhara, S. Takizawa, C. V. Y. D. Strihou, and T. Miyata, “Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model,” Nephrology Dialysis Transplantation, vol. 23, no. 4, pp. 1166–1172, 2008.
[30]
E. Conde, L. Alegre, I. Blanco-Sánchez et al., “Hypoxia inducible factor 1-alpha (hif-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival,” PLoS ONE, vol. 7, no. 3, Article ID e33258, 2012.
[31]
E. C. Leonard, J. L. Friedrich, and D. P. Basile, “VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury,” American Journal of Physiology, vol. 295, no. 6, pp. F1648–F1657, 2008.
