The Effects of Insulin Resistance and Inflammation on Renal Proximal Tubule Sodium Transport and Hypertension


Insulin resistance, closely linked to inflammation, is recognized as a key factor in the onset and aggravation of diabetes, cardio-renal syndrome, hypertension, and obesity. In the renal proximal tubule, insulin resistance may increase renal sodium reabsorption, leading to hypertension, edema and sometimes heart failure. Recently some anti-diabetic agents have been shown to have effects on the transporters in renal proximal tubule. Because renal proximal tubule mediates about 70% of sodium reabsorption, it is quite important to clarify the function of renal proximal tubule under insulin resistance and inflammation.

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S. Horita, M. Nakamura, M. Suzuki, H. Yamada and G. Seki, "The Effects of Insulin Resistance and Inflammation on Renal Proximal Tubule Sodium Transport and Hypertension," Open Journal of Endocrine and Metabolic Diseases, Vol. 3 No. 5A, 2013, pp. 34-41. doi: 10.4236/ojemd.2013.35A003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] S. E. Shoelson, J. Lee and A. B. Goldfine, “Inflammation and Insulin Resistance,” Journal of Clinical Investigation, Vol. 116, No. 7, 2006, pp. 1793-1801. doi:10.1172/JCI29069
[2] W. Ebstein, “Invited Comment on W. Ebstein: On the Therapy of Diabetes Mellitus, in Particular on the Application of Sodium Salicylate,” Journal of Molecular Medicine (Berlin), Vol. 80, No. 10, 2002, pp. 618-619.
[3] R. T. Williamson, “On the Treatment of Glycosuria and Diabetes Mellitus with Sodium Salicylate,” British Medical Journal, Vol. 1, No. 2100, 1901, pp. 760-762. doi:10.1136/bmj.1.2100.760
[4] G. S. Hotamisligil, N. S. Shargill and B. M. Spiegelman, “Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance,” Science, Vol. 259, No. 5091, 1993, pp. 87-91. doi:10.1126/science.7678183
[5] R. Feinstein, H. Kanety, M. Z. Papa, B. Lunenfeld and A. Karasik, “Tumor Necrosis Factor-α Suppresses InsulinInduced Tyrosine phosphorylation of Insulin Receptor and Its Substrates,” The Journal of Biological Chemistry, Vol. 268, 1993, pp. 26055-26058
[6] R. Yang and J. M. Trevillyan, “c-Jun N-Terminal Kinase Pathways in Diabetes,” The International Journal of Biochemistry & Cell Biology, Vol. 40, No. 12,2008, pp. 2702-2706. doi:10.1016/j.biocel. 2008. 06.012
[7] R. J. Davis, “Signal Transduction by the JNK Group of MAP Kinases,” Cell, Vol. 103, No. 2, 2000, pp. 239-252. doi:10.1016/S0092-8674(00)00116-1
[8] V. Aguirre, T. Uchida, L. Yenush, R. Davis and M. F. White, “The c-Jun NH2-Terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser(307),” The Journal of Biological Chemistry, Vol. 275, No. 12, 2000, pp.9047-9054. doi:10.1074/jbc. 275.12.9047
[9] U. Ozcan, Q. Cao, E. Yilmaz, et al., “Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes,” Science, Vol. 306, No. 5695, 2004, pp. 457-461. doi:10.1126/science.1103160
[10] V. Aguirre, E. D. Werner, J. Giraud, Y. H. Lee, S. E. Shoelson and M. F. White, “Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action,” The Journal of Biological Chemistry, Vol. 277, No. 2, 2002, pp. 1531-1537. doi:10.1074/jbc.M101521200
[11] E. D. Werner, J. Lee, L. Hansen, M. Yuan and S. E. Shoelson, “Insulin Resistance Due to Phosphorylation of Insulin Receptor Substrate-1 at Serine 302,” The Journal of Biological Chemistry, Vol. 279, No. 34, 2004, pp. 35298-35305. doi:10.1074/jbc.M405203200
[12] M. S. Han, D. Y. Jung, C. Morel, et al., “ JNK Expression by Macrophages Promotes Obesity-Induced Insulin Resistance and Inflammation,” Science, Vol. 339, No. 6116, 2013, pp. 218-222. doi:10.1126/science.1227568
[13] M. J. Lenardo and D. Baltimore, “NF-κB: A Pleiotropic Mediator of Inducible and Tissue-Specific Gene Control,” Cell, Vol. 58, No. 2, 1989, pp. 227-229. doi:10.1016/0092-8674(89)90833-7
[14] P. J. Barnes and M. Karin, “Nuclear Factor-κB: A Pivotal Transcription Factor in Chronic Inflammatory Diseases,” The New England Journal of Medicine, Vol. 336, No. 15, 1997, pp. 1066-1071. doi:10.1056/NEJM199704103361506
[15] L. W. Chen, L. Egan, Z. W. Li, F. R. Greten, M. F. Kagnoff and M. Karin, “The Two Faces of IKK and NFκB Inhibition: Prevention of Systemic Inflammation but Increased Local Injury Following Intestinal IschemiaReperfusion,” Nature Medicine, Vol. 9, No. 5, 2003, pp. 575-581. doi:10.1038/nm849
[16] M. C. Arkan, A. L. Hevener, F. R. Greten, et al., “ IKK-β Links Inflammation to Obesity-Induced Insulin Resistance,” Nature Medicine, Vol. 11, No. 2, 2005, pp. 191-198. doi:10.1038/nm1185
[17] L. P. Kane, V. S. Shapiro, D. Stokoe and A. Weiss, “Induction of NF-κB by the Akt/PKB Kinase,” Current Biology, Vol. 9, No. 11, 1999, pp. 601-604. doi:10.1016/S0960-9822(99)80265-6
[18] O. N. Ozes, L. D. Mayo, J. A. Gustin, S. R. Pfeffer, L. M. Pfeffer and D. B. Donner, “NF-κB Activation by Tumour Necrosis Factor Requires the Akt Serine-Threonine Kinase,” Nature, Vol. 401, No. 6748, 1999, pp. 82-85. doi:10.1038/43466
[19] A. Salminen and K. Kaarniranta, “Insulin/IGF-1 Paradox of Aging: Regulation via AKT/IKK/NF-κB Signaling,” Cell Signal, Vol. 22, No. 4, 2010, pp. 573-577. doi:10.1016/j.cellsig.2009.10.006
[20] E. A. Carswell, L. J. Old, R. L. Kassel, S. Green, N. Fiore and B. Williamson, “An Endotoxin-Induced Serum Factor That Causes Necrosis of Tumors,” Proceedings of the National Academy of Sciences of USA, Vol. 72, No. 9, 1975, pp. 3666-3670. doi:10.1073/pnas.72.9.3666
[21] Y. Ichinose, J. Y. Tsao and I. J. Fidler, “Destruction of Tumor Cells by Monokines Released from Activated Human Blood Monocytes: Evidence for Parallel and Additive Effects of IL-1 and TNF,” Cancer Immunology, Immunotherapy, Vol. 27, No. 1, 1988, pp. 7-12. doi:10.1007/BF00205751
[22] B. Beutler, D. Greenwald, J. D. Hulmes, et al., “Identity of Tumour Necrosis Factor and the Macrophage-Secreted Factor Cachectin,” Nature, Vol. 316, No. 6028, 1985, pp. 552-554. doi:10.1038/316552a0
[23] P. G. Tipping, T. W. Leong and S. R. Holdsworth, “Tumor Necrosis Factor Production by Glomerular Macrophages in Anti-Glomerular Basement Membrane Glomerulonephritis in Rabbits,” Laboratory Investigation, Vol. 65, 1991, pp. 272-279.
[24] V. D. Ramseyer and J. L. Garvin, “Tumor Necrosis Factor-α: Regulation of Renal Function and Blood Pressure,” American Journal of Physiology. Renal Physiology, Vol. 304, No. 10, 2013, pp. F1231-F1242. doi:10.1152/ajprenal.00557.2012
[25] X. Dong, S. Swaminathan, L. A. Bachman, A. J. Croatt, K. A. Nath and M. D. Griffin, “Resident Dendritic Cells Are the Predominant TNF-Secreting Cell in Early Renal Ischemia-Reperfusion Injury,” Kidney International, Vol. 71, No. 7, 2007, pp. 619-628. doi:10.1038/
[26] L. Baud, J. P. Oudinet, M. Bens, et al., “ Production of Tumor Necrosis Factor by Rat Mesangial Cells in Response to Bacterial Lipopolysaccharide,” Kidney International, Vol. 35, No. 5, 1989, pp. 1111-1118. doi:10.1038/ki.1989.98
[27] M. Ruiz-Ortega, V. Esteban, M. Rupérez, et al., “Renal and Vascular Hypertension-Induced Inflammation: Role of Angiotensin II,” Current Opinion in Nephrology and Hypertension, Vol. 15, No. 2, 2006, pp. 159-166. doi:10.1097/01.mnh.0000203190.34643.d4
[28] G. I. Botchkina, M. E. Meistrell, I. L. Botchkina and K. J. Tracey, “Expression of TNF and TNF Receptors (p55 and p75) in the Rat Brain after Focal Cerebral Ischemia,” Molecular Medicine, Vol. 3, No. 11, 1997, pp. 765-781.
[29] X. J. Sun, L. M. Wang, Y. Zhang, et al., “Role of IRS-2 in Insulin and Cytokine Signalling,” Nature, Vol. 377, No. 6545, 1995, pp. 173-177. doi:10.1038/377173a0
[30] R. S. Al-Lamki, J. Wang, J. N. Skepper, S. Thiru, J. S. Pober and J. R. Bradley, “Expression of Tumor Necrosis Factor Receptors in Normal Kidney and Rejecting Renal Transplants,” Laboratory Investigation, Vol. 81, No. 11, 2001, pp. 1503-1515. doi:10.1038/labinvest.3780364
[31] L. A. Tartaglia, R. F. Weber, I. S. Figari, C. Reynolds, M. A. Palladino and D. V. Goeddel, “The Two Different Receptors for Tumor Necrosis Factor Mediate Distinct Cellular Responses,” Proceedings of the National Academy of Sciences of USA, Vol. 88, No. 20, 1991, pp. 9292-9296. doi:10. 1073/pnas.88.20. 9292
[32] M. Feldmann, “Many Cytokines Are Very Useful Therapeutic Targets in Disease,” Journal of Clinical Investigation, Vol. 118, No. 11, 2008, pp. 3533-3536. doi:10.1172/JCI37346
[33] N. Defer, A. Azroyan, F. Pecker and C. Pavoine, “TNFR1 and TNFR2 Signaling Interplay in Cardiac Myocytes,” The Journal of Biological Chemistry, Vol. 282, No. 49, 2007, pp. 35564-35573. doi:10.1074/jbc.M704003200
[34] Y. Zhang, J. Zhao, W. B. Lau, et al., “Tumor Necrosis Factor-α and Lymphotoxin-α Mediate Myocardial Ischemic Injury via TNF Receptor 1, but Are Cardioprotective When Activating TNF Receptor 2,” PLoS One, Vol. 8, 2013, Article ID: e60227. doi:10.1371/journal.pone.0060227
[35] A. Castillo, M. T. Islam, M. C. Prieto and D. S. Majid, “Tumor Necrosis Factor-α Receptor Type 1, Not Type 2, Mediates Its Acute Responses in the Kidney,” American Journal of Physiology. Renal Physiology, Vol. 302, No. 12, 2012, pp. F1650-F1657. doi:10.1152/ajprenal.00426.2011
[36] P. Singh, L. Bahrami, A. Castillo and D. S. Majid, “TNFα Type 2 Receptor Mediates Renal Inflammatory Response to Chronic Angiotensin II Administration with High Salt Intake in Mice,” American Journal of Physiology—Renal Physiology, Vol. 304, No. 7, 2013, pp. F991-F999. doi:10.1152/ajprenal. 00525.2012
[37] K. DiPetrillo, B. Coutermarsh, N. Soucy, J. Hwa and F. Gesek, “Tumor Necrosis Factor Induces Sodium Retention in Diabetic Rats through Sequential Effects on Distal Tubule Cells,” Kidney International, Vol. 65, No. 5, 2004, pp. 1676-1683. doi:10.1111/j.1523-1755.2004.00606.x
[38] K. DiPetrillo, B. Coutermarsh and F. A. Gesek, “Urinary Tumor Necrosis Factor Contributes to Sodium Retention and Renal Hypertrophy during Diabetes,” American Journal of Physiology—Renal Physiology, Vol. 284, No. 1, 2003, pp. F113-F121.
[39] N. F. Ramia and S. I. Kreydiyyeh, “TNF-α Modulates the Na+/ K+ ATPase and the Na+-K+-2Cl? Symporter in LLCPK Cells,” European Journal of Clinical Investigation, Vol. 39, No. 4, 2009, pp. 280-288. doi:10.1111/j.1365-2362.2009.02098.x
[40] C. C. Chen, P. L. Pedraza, S. Hao, C. T. Stier and N. R. Ferreri, “TNFR1-Deficient Mice Display Altered Blood Pressure and Renal Responses to ANG II Infusion,” American Journal of Physiology—Renal Physiology, Vol. 299, No. 5, 2010, pp. F1141-F1150. doi:10.1152/ajprenal.00344.2010
[41] D. Brown and C. A. Wagner, “Molecular Mechanisms of Acid-Base Sensing by the Kidney,” Journal of the American Society of Nephrology, Vol. 23, No. 5, 2012, pp. 774-780. doi:10.1681/ASN.2012010029
[42] L. A. Skelton, W. F. Boron and Y. Zhou, “Acid-Base Transport by the Renal Proximal Tubule,” Journal of Nephrology, Vol. 23, Suppl. 16, 2010, pp. S4-S18.
[43] W. F. Boron, “Acid-Base Transport by the Renal Proximal Tubule,” Journal of the American Society of Nephrology, Vol. 17, No. 9, 2006, pp. 2368-2382. doi:10.1681/ASN.2006060620
[44] J. E. Bourdeau, E. R. Chen and F. A. Carone, “Insulin Uptake in the Renal Proximal Tubule,” American Journal of Physiology, Vol. 225, No. 6, 1973, pp. 1399-1404.
[45] M. A. Cortney, L. L. Sawin and D. D. Weiss, “Renal Tubular Protein Absorption in the Rat,” Journal of Clinical Investigation, Vol. 49, No. 1, 1970, pp. 1-4. doi:10.1172/JCI106208
[46] R. Rabkin, A. H. Rubenstein and J. A. Colwell, “Glomerular Filtration and Proximal Tubular Absorption of Insulin 125 I,” American Journal of Physiology, Vol. 223, No. 5, 1972, pp. 1093-1096.
[47] R. A. DeFronzo, C. R. Cooke, R. Andres, G. R. Faloona and P. J. Davis, “The Effect of Insulin on Renal Handling of Sodium, Potassium, Calcium, and Phosphate in Man,” Journal of Clinical Investigation, Vol. 55, No. 4, 1975, pp. 845-855. doi:10.1172/JCI107996
[48] R. A. DeFronzo, M. Goldberg and Z. S. Agus, “The Effects of Glucose and Insulin on Renal Electrolyte Transport,” Journal of Clinical Investigation, Vol. 58, No. 1, 1976, pp. 83-90. doi:10.1172/JCI108463
[49] F. A. Gesek and A. C. Schoolwerth, “Insulin Increases Na+-H+ Exchange Activity in Proximal Tubules from Normotensive and Hypertensive Rats,” American Journal of Physiology, Vol. 260, No. 5, 1991, pp. F695-F703.
[50] E. Feraille, M. L. Carranza, M. Rousselot and H. Favre, “Insulin Enhances Sodium Sensitivity of Na-K-ATPase in Isolated Rat Proximal Convoluted Tubule,” American Journal of Physiology, Vol. 267, No. 1, 1994, F55-F62.
[51] C. Rivera, H. Reyes-Santos and M. Marinez-Maldonado, “Response of Dog Renal Na+, K+-ATPase to Insulin in Vitro,” Renal Physiology, Vol. 1, No. 1, 1978, pp. 74-83.
[52] Z. Taylor, D. S. Emmanouel and A. I. Katz, “Insulin Stimulates Na-K-ATPase Activity of Basolateral Renal Tubular Membranes (Abstract),” Kidney International, Vol. 21, No. 1, 1982, p. 266.
[53] O. S. Ruiz, Y. Y. Qiu, L. R. Cardoso and J. A. Arruda, “Regulation of the Renal Na-HCO3 Cotransporter: IX. Modulation by Insulin, Epidermal Growth Factor and Carbachol,” Regulatory Peptides, Vol. 77, No. 1-3, 1998, pp. 155-161. doi:10.1016/S0167-0115(98)00115-3
[54] Y. Zheng, H. Yamada, K. Sakamoto, et al., “Roles of Insulin Receptor Substrates in Insulin-Induced Stimulation of Renal Proximal Bicarbonate Absorption,” Journal of the American Society of Nephrology, Vol. 16, No. 8, 2005, pp. 2288-2295. doi:10.1681/ASN.2005020193
[55] E. Carvalho, P. A. Jansson, M. Axelsen, et al., “Low Cellular IRS 1 Gene and Protein Expression Predict Insulin Resistance and NIDDM,” The FASEB Journal, Vol. 13, No. 15, 1999, pp. 2173-2178.
[56] J. E. Friedman, T. Ishizuka, J. Shao, L. Huston, T. Highman and P. Catalano, “Impaired Glucose Transport and Insulin Receptor Tyrosine Phosphorylation in Skeletal Muscle from Obese Women with Gestational Diabetes,” Diabetes, Vol.48, No. 9,1999, pp. 807-1814. doi:10.2337/diabetes.48.9. 1807
[57] L. J. Goodyear, F. Giorgino, L. A. Sherman, J. Carey, R. J. Smith and G. L. Dohm, “Insulin Receptor Phosphorylation, Insulin Receptor Substrate-1 Phosphorylation, and Phosphatidylinositol 3-Kinase Activity Are Decreased in Intact Skeletal Muscle Strips from Obese Subjects,” Journal of Clinical Investigation, Vol. 95, No. 5, 1995, pp. 2195-2204. doi:10.1172/JCI117909
[58] C. M. Rondinone, L. M. Wang, P. Lonnroth, C. Wesslau, J. H. Pierce and U. Smith, “Insulin Receptor Substrate (IRS) 1 Is Reduced and IRS-2 is the Main Docking Protein for Phosphatidylinositol 3-Kinase in Adipocytes from Subjects with Non-Insulin-Dependent Diabetes Mellitus,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 8, 1997, pp. 4171-4175. doi:10.1073/pnas.94.8.4171
[59] H. Abe, N. Yamada, K. Kamata, et al., “Hypertension, Hypertriglyceridemia, and Impaired Endothelium-Dependent Vascular Relaxation in Mice Lacking Insulin Receptor Substrate-1,” Journal of Clinical Investigation, Vol. 101, No. 8, 1998, pp. 1784-1788. doi:10.1172/JCI1594
[60] H. Dimke, “Exploring the Intricate Regulatory Network Controlling the Thiazide-Sensitive NaCl Cotransporter (NCC),” Pflugers Arch, Vol. 462, No. 6, 2011, pp. 767-777. doi:10.1007/s00424-011-1027-1
[61] B. Xu, J. M. English, J. L. Wilsbacher, S. Stippec, E. J. Goldsmith and M. H. Cobb, “WNK1, a Novel Mammalian Serine/Threonine Protein Kinase Lacking the Catalytic Lysine in Subdomain II,” The Journal of Biological Chemistry, Vol. 275, No. 22, 2000, pp. 16795-16801. doi:10.1074/jbc.275.22.16795
[62] J. A. McCormick, C. L. Yang and D. H. Ellison, “WNK Kinases and Renal Sodium Transport in Health and Disease: An Integrated View,” Hypertension, Vol. 51, No. 3, 2008, pp. 588-596. doi:10.1161/HYPERTENSIONAHA.107.103788
[63] F. H. Wilson, S. Disse-Nicodème, K. A. Choate, et al., “Human Hypertension Caused by Mutations in WNK Kinases,” Science, 2001; Vol. 293, No. 5532, pp. 1107-1112. doi:10.1126/science.1062844
[64] H. Cai, V. Cebotaru, Y. H. Wang, et al., “WNK4 Kinase Regulates Surface Expression of the Human Sodium Chloride Cotransporter in Mammalian Cells,” Kidney International, Vol. 69, No. 12, 2006, pp. 2162-2170. doi:10.1038/
[65] A. P. Golbang, G. Cope, A. Hamad, et al., “Regulation of the Expression of the Na/Cl Cotransporter by WNK4 and WNK1: Evidence That Accelerated Dynamin-Dependent Endocytosis Is Not Involved,” American Journal of Physiology—Renal Physiology, Vol. 291, No. 6, 2006, pp. F1369-F1376. doi:10.1152/ajprenal.00468.2005
[66] M. E. Safar and H. S. Boudier, “Vascular Development, Pulse Pressure, and the Mechanisms of Hypertension,” Hypertension, Vol. 46, No.1, 2005, pp. 205-209. doi:10.1161/01.HYP. 0000167992 .80876.26
[67] C. L. Yang, J. Angell, R. Mitchell and D. H. Ellison, “WNK kinases regulate thiazide-sensitive Na-Cl cotransport,” Journal of Clinical Investigation, Vol. 111, No. 7, 2003, pp. 1039-1045.
[68] A. Ohta, T. Rai, N. Yui, et al., “Targeted Disruption of the Wnk4 Gene Decreases Phosphorylation of Na-Cl Cotransporter, Increases Na Excretion and Lowers Blood Pressure,” Human Molecular Genetics, Vol. 18, No. 20, 2009, pp. 3978-3986. doi:10.1093/hmg/ddp344
[69] M. Wakabayashi, T. Mori, K. Isobe, et al., “Impaired KLHL3-Mediated Ubiquitination of WNK4 Causes Human Hypertension,” Cell Reports, Vol. 3, No. 3, 2013, pp. 858-868. doi:10.1016/j.celrep. 2013.02.024
[70] E. Sohara, T. Rai, S. S. Yang, et al., “Acute Insulin Stimulation Induces Phosphorylation of the Na-Cl Cotransporter in Cultured Distal mpkDCT Cells and Mouse Kidney,” PLoS ONE, Vol. 6, No. 8, 2011, Article ID: e24277. doi:10.1371/journal.pone.0024277
[71] H. Nishida, E. Sohara, N. Nomura, et al., “Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice,” Hypertension, Vol. 60, No. 4, 2012, pp. 981-990. doi:10.1161/HYPERTENSIONAHA.112.201509
[72] M. Chávez-Canales, J. P. Arroyo, B. Ko, et al., “Insulin Increases the Functional Activity of the Renal NaCl Cotransporter,” Journal of Hypertension, Vol. 31, No. 2, 2013, pp. 303-311.
[73] H. Yki-Jarvinen, “Thiazolidinediones,” The New England Journal of Medicine, Vol. 351, 2004, pp. 1106-1118. doi:10.1056/NEJMra041001
[74] R. M. Lago, P. P. Singh and R. W. Nesto, “Congestive Heart Failure and Cardiovascular Death in Patients with Prediabetes and Type 2 Diabetes Given Thiazolidinediones: A Meta-Analysis of Randomised Clinical Trials,” Lancet, Vol. 370, No. 9593, 2007, pp. 1129-1136. doi:10.1016/S0140-6736(07)61514-1
[75] E. Erdmann, B. Charbonnel, R. G. Wilcox, et al., “Pioglitazone Use and Heart Failure in Patients with Type 2 Diabetes and Preexisting Cardiovascular Disease: Data from the PROactive Study (PROactive 08),” Diabetes Care, Vol. 30, No. 11, 2007, pp. 2773-2778. doi:10.2337/dc07-0717
[76] J. D. Lewis, A. Ferrara, T. Peng, et al., “Risk of Bladder Cancer among Diabetic Patients Treated with Pioglitazone: Interim Report of a Longitudinal Cohort Study,” Diabetes Care, Vol. 34, No. 4, 2011, pp. 916-922. doi:10.2337/dc10-1068
[77] H. Zhang, A. Zhang, D. E. Kohan, R. D. Nelson, F. J. Gonzalez and T. Yang, “Collecting Duct-Specific Deletion of Peroxisome Proliferator-Activated Receptor γ Blocks Thiazolidinedione-Induced Fluid Retention,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 26, 2005, pp. 9406-9411. doi:10.1073/pnas.0501744102
[78] Y. Guan, C. Hao, D. R. Cha, et al., “Thiazolidinediones Expand Body Fluid Volume through PPARγ Stimulation of ENaC-Mediated Renal Salt Absorption,” Nature Medicine, Vol. 11, No. 8, 2005, pp. 861-866. doi:10.1038/nm1278
[79] G. Hong, A. Lockhart, B. Davis, et al., “PPARγ Activation Enhances Cell Surface ENaCalpha via Up-Regulation of SGK1 in Human Collecting Duct Cells,” The FASEB Journal, Vol. 17, No. 13, 2003, pp. 1966-1968.
[80] C. Nofziger, L. Chen, M. A. Shane, C. D. Smith, K. K. Brown and B. L. Blazer-Yost, “PPARγ Agonists Do Not Directly Enhance Basal or Insulin-Stimulated Na+ Transport via the Epithelial Na+ Channel,” Pflügers Archiv, Vol. 451, No. 3, 2005, pp. 445-453. doi:10.1007/s00424-005-1477-4
[81] J. Song, M. A. Knepper, X. Hu, J. G. Verbalis and C. A. Ecelbarger, “Rosiglitazone Activates Renal Sodiumand Water-Reabsorptive Pathways and Lowers Blood Pressure in Normal Rats,” Journal of Pharmacology and Experimental Therapeutics, Vol. 308, No. 2, 2004, pp. 426-433. doi:10.1124/jpet.103.058008
[82] L. Chen, B. Yang, J. A. McNulty, et al., “GI262570, a Peroxisome Proliferator-Activated Receptor γ Agonist, Changes Electrolytes and Water Reabsorption from the Distal Nephron in Rats,” Journal of Pharmacology and Experimental Therapeutics, Vol. 312, No. 2, 2005, pp. 718-725. doi:10.1124/jpet.104.074088
[83] V. Vallon, E. Hummler, T. Rieg, et al., “Thiazolidinedione-Induced Fluid Retention Is Independent of Collecting Duct αENaC Activity,” Journal of the American Society of Nephrology, Vol. 20, No. 4, 2009, pp. 721-729. doi:10.1681/ASN.2008040415
[84] A. Zanchi, A. Chiolero, M. Maillard, J. Nussberger, H. R. Brunner and M. Burnier, “Effects of the Peroxisomal Proliferator-Activated Receptor-γ Agonist Pioglitazone on Renal and Hormonal Responses to Salt in Healthy Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 89, No. 3, 2004, pp. 1140-1145. doi:10.1210/jc.2003-031526
[85] S. Muto, Y. Miyata, M. Imai and Y. Asano, “Troglitazone Stimulates Basolateral Rheogenic Na+/ Cotransport Activity in Rabbit Proximal Straight Tubules,” Experimental Nephrology, Vol. 9, No. 3, 2001, pp. 191-197.
[86] Y. Endo, M. Suzuki, H. Yamada, et al., “Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling,” Cell Metabolism, Vol. 13, No. 5, 2011, pp. 550-561. doi:10.1016/j.cmet.2011.02.015
[87] E. Borsting, V. P. Cheng, C. K. Glass, V. Vallon and R. Cunard, “Peroxisome Proliferator-Activated Receptor-γ Agonists Repress Epithelial Sodium Channel Expression in the Kidney,” American Journal of Physiology—Renal Physiology, Vol. 302, No. 5, 2012, pp. F540-F551. doi:10.1152/ajprenal.00306.2011
[88] G. S. Hotamisligil, “Inflammation and Metabolic Disorders,” Nature, Vol. 444, No. 7121, 2006, pp. 860-867. doi:10.1038/nature05485
[89] I. Barroso, M. Gurnell, V. E. Crowley, et al., “Dominant Negative Mutations in Human PPARγ Associated with Severe Insulin Resistance, Diabetes Mellitus and Hypertension,” Nature, Vol. 402, No. 6764, 1999, pp. 880-883
[90] S. S. Deeb, L. Fajas, M. Nemoto, et al., “A Pro12Ala Substitution in PPARγ2 Associated with Decreased Receptor Activity, Lower Body Mass Index and Improved Insulin Sensitivity,” Nature Genetics, Vol. 20, No. 3, 1998, pp. 284-287. doi:10.1038/3099
[91] S. M. Rangwala, B. Rhoades, J. S. Shapiro, et al., “Genetic Modulation of PPARγ Phosphorylation Regulates Insulin Sensitivity,” Developmental Cell, Vol. 5, No. 4, 2003, pp. 657-663. doi:10.1016/S1534-5807(03)00274-0
[92] W. He, Y. Barak, A. Hevener, et al., “Adipose-Specific Peroxisome Proliferator-Activated Receptor γ Knockout Causes Insulin Resistance in Fat and Liver but Not in Muscle,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 26, 2003, pp. 15712-15717.
[93] K. Matsusue, M. Haluzik, G. Lambert, et al., “LiverSpecific Disruption of PPARγ in Leptin-Deficient mice Improves Fatty Liver but Aggravates Diabetic Phenotypes,” Journal of Clinical Investigation, Vol. 111, No. 5, 2003, pp. 737-747.
[94] A. W. Norris, L. Chen, S. J. Fisher, et al., “Muscle-Specific PPARγ-Deficient Mice Develop Increased Adiposity and Insulin Resistance but Respond to Thiazolidinediones,” Journal of Clinical Investigation, Vol. 112, No. 4, 2003, pp. 608-618. doi:10.1073/pnas.2536828100
[95] A. L. Hevener, W. He, Y. Barak, et al., “Muscle-Specific PPARγ Deletion Causes Insulin Resistance,” Nature Medicine, Vol. 9, No. 12, 2003, pp. 1491-1497. doi:10.1038/nm956
[96] M. Lehrke and M. A. Lazar, “The Many Faces of PPARγ,” Cell, Vol. 123, No. 6, 2005, pp. 993-999. doi:10.1016/j.cell.2005.11.026
[97] J. J. Nolan, B. Ludvik, P. Beerdsen, M. Joyce and J. Olefsky, “Improvement in Glucose Tolerance and Insulin Resistance in Obese Subjects Treated with Troglitazone,” The New England Journal of Medicine, Vol. 331, No. 18, 1994, pp. 1188-1193. doi:10.1056/NEJM199411033311803
[98] B. Cariou, B. Charbonnel and B. Staels, “Thiazolidinediones and PPARγ Agonists: Time for a Reassessment,” Trends in Endocrinology & Metabolism, Vol. 23, No. 5, 2012, pp. 205-215. doi:10.1016/j.tem.2012.03.001
[99] D. S. Straus and C. K. Glass, “Anti-Inflammatory Actions of PPAR ligands: New Insights on Cellular and Molecular Mechanisms,” Trends in Immunology, Vol. 28, No. 12, 2007, pp. 551-558. doi:10.1016/
[100] L. Petrica, A. Vlad, M. Petrica, et al., “Pioglitazone Delays Proximal Tubule Dysfunction and Improves Cerebral Vessel Endothelial Dysfunction in Normoalbuminuric People with Type 2 Diabetes Mellitus,” Diabetes Research and Clinical Practice, Vol. 94, No. 1, 2011, pp. 22-32. doi:10.1016/j.diabres.2011.05.032
[101] K. Pegg, J. Zhang, C. Pollock and S. Saad, “Combined Effects of PPARγ Agonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells,” PPAR Research, Vol. 2013, 2013, Article ID: 982462.
[102] W. M. Wang, H. D. Zhang, Y. M. Jin, B. B. Zhu and N. Chen, “PPARγ Agonists Inhibit TGFβ1-Induced Chemokine Expression in Human Tubular Epithelial cells,” Acta Pharmacologica Sinica, Vol. 30, No. 6586, 2009, pp. 107-112. doi:10.1038/aps.2008.15

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