Journal of the American Society of Nephrology, Vol 7, 2202-2212, Copyright © 1996 by American Society of Nephrology

REGULAR ARTICLES

Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy

JJ Morrissey, S Ishidoya, R McCracken and S Klahr
Department of Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

This article has been cited by other articles:

				M. Carlstrom, R. D. Brown, J. Edlund, J. Sallstrom, E. Larsson, T. Teerlink, F. Palm, N. Wahlin, and A. E. G. Persson Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals Am J Physiol Renal Physiol, February 1, 2008; 294(2): F362 - F370. [Abstract] [Full Text] [PDF]

				P. Boor, K. Sebekova, T. Ostendorf, and J. Floege Treatment targets in renal fibrosis Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3391 - 3407. [Full Text] [PDF]

				W.-Y. Lin, R. M. Levin, P. Chichester, R. Leggett, Y.-S. Juan, A. Johnson, P. Neumann, C. Whitbeck, A. Guven, B. Kogan, et al. Effects of L-arginine and L-NAME on chronic partial bladder outlet obstruction in rabbit Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2007; 293(6): R2390 - R2399. [Abstract] [Full Text] [PDF]

				N. G. Docherty, O. E. O'Sullivan, D. A. Healy, J. M. Fitzpatrick, and R. W. G. Watson Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction Am J Physiol Renal Physiol, January 1, 2006; 290(1): F4 - F13. [Abstract] [Full Text] [PDF]

				K. Ito, J. Chen, M. El Chaar, J. M. Stern, S. V. Seshan, J. J. Khodadadian, I. Richardson, M. J. Hyman, E. D. Vaughan Jr., D. P. Poppas, et al. Renal damage progresses despite improvement of renal function after relief of unilateral ureteral obstruction in adult rats Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1283 - F1293. [Abstract] [Full Text] [PDF]

				G. Cherla and E. A. Jaimes Role of L-Arginine in the Pathogenesis and Treatment of Renal Disease J. Nutr., October 1, 2004; 134(10): 2801S - 2806S. [Abstract] [Full Text] [PDF]

				J. M. Stern, J. Chen, R. B. Silver, D. P. Poppas, E. D. Vaughan Jr., and D. Felsen Effect of UUO on D1aR expression reveals a link among dopamine, transforming growth factor-{beta}, and nitric oxide Am J Physiol Renal Physiol, March 1, 2004; 286(3): F509 - F515. [Abstract] [Full Text]

				N. Sadamasa, K. Nozaki, and N. Hashimoto Disruption of Gene for Inducible Nitric Oxide Synthase Reduces Progression of Cerebral Aneurysms Stroke, December 1, 2003; 34(12): 2980 - 2984. [Abstract] [Full Text] [PDF]

				D. P. Basile, D. L. Donohoe, K. Roethe, and D. L. Mattson Chronic renal hypoxia after acute ischemic injury: effects of L-arginine on hypoxia and secondary damage Am J Physiol Renal Physiol, February 1, 2003; 284(2): F338 - F348. [Abstract] [Full Text] [PDF]

				K. Moridaira, J. Morrissey, M. Fitzgerald, G. Guo, R. McCracken, T. Tolley, and S. Klahr ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction Am J Physiol Renal Physiol, January 1, 2003; 284(1): F209 - F217. [Abstract] [Full Text] [PDF]

				S. Klahr and J. Morrissey Obstructive nephropathy and renal fibrosis Am J Physiol Renal Physiol, November 1, 2002; 283(5): F861 - F875. [Abstract] [Full Text] [PDF]

				J. Morrissey, K. Hruska, G. Guo, S. Wang, Q. Chen, and S. Klahr Bone Morphogenetic Protein-7 Improves Renal Fibrosis and Accelerates the Return of Renal Function J. Am. Soc. Nephrol., January 1, 2002; 13(90001): S14 - 21. [Abstract] [Full Text] [PDF]

				M. SATOH, N. KASHIHARA, Y. YAMASAKI, K. MARUYAMA, K. OKAMOTO, Y. MAESHIMA, H. SUGIYAMA, T. SUGAYA, K. MURAKAMI, and H. MAKINO Renal Interstitial Fibrosis Is Reduced in Angiotensin II Type 1a Receptor-Deficient Mice J. Am. Soc. Nephrol., February 1, 2001; 12(2): 317 - 325. [Abstract] [Full Text]

				I. H. C. VOS, T. J. RABELINK, B. DORLAND, R. LOOS, B. V. MIDDELAAR, H.-J. GRÖNE, and J. A. JOLES L-Arginine Supplementation Improves Function and Reduces Inflammation in Renal Allografts J. Am. Soc. Nephrol., February 1, 2001; 12(2): 361 - 367. [Abstract] [Full Text]

				J. MORRISSEY, G. GUO, R. MCCRACKEN, T. TOLLEY, and S. KLAHR Induction of CD14 in Tubular Epithelial Cells During Kidney Disease J. Am. Soc. Nephrol., September 1, 2000; 11(9): 1681 - 1690. [Abstract] [Full Text]

				J. J. Morrissey and S. Klahr Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis Am J Physiol Renal Physiol, January 1, 1999; 276(1): F39 - F45. [Abstract] [Full Text] [PDF]

				J. E. Toblli, I. Stella, E. de Cavanagh, M. Angerosa, F. Inserra, and L. Ferder Enalapril Prevents Tubulointerstitial Lesions by Hyperoxaluria Hypertension, January 1, 1999; 33(1): 225 - 231. [Abstract] [Full Text] [PDF]

				C. M. Hogaboam, C. S. Gallinat, C. Bone-Larson, S. W. Chensue, N. W. Lukacs, R. M. Strieter, and S. L. Kunkel Collagen Deposition in a Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition Am. J. Pathol., December 1, 1998; 153(6): 1861 - 1872. [Abstract] [Full Text] [PDF]

				J. J. Morrissey and S. Klahr Differential effects of ACE and AT1 receptor inhibition on chemoattractant and adhesion molecule synthesis Am J Physiol Renal Physiol, March 1, 1998; 274(3): F580 - F586. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673