Published online before print April 24, 2006, doi: 10.1161/01.HYP.0000222003.28517.99
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2006;47:1084.)
© 2006 American Heart Association, Inc.
Original Articles |
Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker
From the Departments of Nephrology and Endocrinology (M.N., S.S., S.Y., T.G., T.F.) and Plastic and Reconstructive Surgery (T.N.), University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Correspondence to Miki Nagase, Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail mnagase-tky{at}umin.ac.jp
Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week–old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.
Key Words: kidney • proteinuria • glomerulosclerosis • aldosterone • mineralocorticoids
This article has been cited by other articles:
 |
|
 |
|
  S. H. Lee, T.-H. Yoo, B.-Y. Nam, D. K. Kim, J. J. Li, D.-S. Jung, S.-J. Kwak, D.-R. Ryu, S. H. Han, J. E. Lee, et al. Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1381 - F1390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Du, Y.-Y. Fan, H. Hitomi, H. Kiyomoto, S. Kimura, C.-Z. Kong, T. Noma, M. Kohno, A. Nishiyama, and D. Nakano Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats Am J Physiol Renal Physiol, September 1, 2009; 297(3): F802 - F808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ritz and A. Tomaschitz Aldosterone, a vasculotoxic agent--novel functions for an old hormone Nephrol. Dial. Transplant., August 1, 2009; 24(8): 2302 - 2305. [Full Text] [PDF]
|
|
|
|
|
|
U. Sen, P. Basu, O. A. Abe, S. Givvimani, N. Tyagi, N. Metreveli, K. S. Shah, J. C. Passmore, and S. C. Tyagi Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure Am J Physiol Renal Physiol, August 1, 2009; 297(2): F410 - F419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cortinovis, N. Perico, D. Cattaneo, and G. Remuzzi Aldosterone and progression of kidney disease Therapeutic Advances in Cardiovascular Disease, April 1, 2009; 3(2): 133 - 143. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Remuzzi, D. Cattaneo, and N. Perico The Aggravating Mechanisms of Aldosterone on Kidney Fibrosis J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1459 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Koop, M. Eikmans, M. Wehland, H. Baelde, D. Ijpelaar, R. Kreutz, H. Kawachi, D. Kerjaschki, E. de Heer, and J. A. Bruijn Selective Loss of Podoplanin Protein Expression Accompanies Proteinuria and Precedes Alterations in Podocyte Morphology in a Spontaneous Proteinuric Rat Model Am. J. Pathol., August 1, 2008; 173(2): 315 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, D. Babankova, J. Huang, G. M. Swain, and D. H. Wang Deletion of Transient Receptor Potential Vanilloid Type 1 Receptors Exaggerates Renal Damage in Deoxycorticosterone Acetate-Salt Hypertension Hypertension, August 1, 2008; 52(2): 264 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsui, K. Ando, H. Kawarazaki, A. Nagae, M. Fujita, T. Shimosawa, M. Nagase, and T. Fujita Salt Excess Causes Left Ventricular Diastolic Dysfunction in Rats With Metabolic Disorder Hypertension, August 1, 2008; 52(2): 287 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-S. Zhou, I. H. Schuman, E. A. Jaimes, and L. Raij Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-{beta}, and fibronectin with concomitant increase in nitric oxide bioavailability Am J Physiol Renal Physiol, July 1, 2008; 295(1): F53 - F59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Piecha, N. Koleganova, M.-L. Gross, A. Geldyyev, M. Adamczak, and E. Ritz Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination Am J Physiol Renal Physiol, July 1, 2008; 295(1): F137 - F144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Huang, C. Xu, K. W. Kahng, N. A. Noble, W. A. Border, and Y. Huang Aldosterone and TGF-{beta}1 synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1287 - F1295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Nakhoul, E. Khankin, A. Yaccob, H. Kawachi, T. Karram, H. Awaad, N. Nakhoul, A. Hoffman, and Z. Abassi Eplerenone potentiates the antiproteinuric effects of enalapril in experimental nephrotic syndrome Am J Physiol Renal Physiol, March 1, 2008; 294(3): F628 - F637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Oba, M. Hino, and T. Fujita Adrenomedullin protects against oxidative stress-induced podocyte injury as an endogenous antioxidant Nephrol. Dial. Transplant., February 1, 2008; 23(2): 510 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Knight, J. E. Quigley, J. Yuan, S. S. Roy, A. Elmarakby, and J. D. Imig Endothelial Dysfunction and the Development of Renal Injury in Spontaneously Hypertensive Rats Fed a High-Fat Diet Hypertension, February 1, 2008; 51(2): 352 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Fujita Insulin resistance and salt-sensitive hypertension in metabolic syndrome Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3102 - 3107. [Full Text] [PDF]
|
|
|
|
|
|
M. Nagase, H. Matsui, S. Shibata, T. Gotoda, and T. Fujita Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor: Role of Oxidative Stress Hypertension, November 1, 2007; 50(5): 877 - 883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shibata, M. Nagase, S. Yoshida, H. Kawachi, and T. Fujita Podocyte as the Target for Aldosterone: Roles of Oxidative Stress and Sgk1 Hypertension, February 1, 2007; 49(2): 355 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nagase, S. Yoshida, S. Shibata, T. Nagase, T. Gotoda, K. Ando, and T. Fujita Enhanced Aldosterone Signaling in the Early Nephropathy of Rats with Metabolic Syndrome: Possible Contribution of Fat-Derived Factors J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3438 - 3446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Opocensky, H. J. Kramer, A. Backer, Z. Vernerova, V. Eis, L. Cervenka, V. Certikova Chabova, V. Tesar, and I. Vaneckova Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension Hypertension, November 1, 2006; 48(5): 965 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Barton, J. J. Mullins, M. A. Bailey, and M. Kretzler Role of Endothelin Receptors for Renal Protection and Survival in Hypertension: Waiting for Clinical Trials Hypertension, November 1, 2006; 48(5): 834 - 837. [Full Text] [PDF]
|
|