This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Benigni, A. Articles by Remuzzi, G. Search for Related Content PubMed PubMed Citation Articles by Benigni, A. Articles by Remuzzi, G.

(American Journal of Pathology. 2001;159:1743-1750.)
© 2001 American Society for Investigative Pathology

Regular Articles

Angiotensin-Converting Enzyme nhibition Prevents Glomerular-Tubule Disconnection and Atrophy in Passive Heymann Nephritis, an Effect Not Observed with a Calcium Antagonist

Ariela Benigni^*, Elena Gagliardini^*, Andrea Remuzzi^*, Daniela Corna^* and Giuseppe Remuzzi^*

From the Mario Negri Institute for Pharmacological Research,^*
Bergamo; and the Unit of Nephrology and Dialysis,
Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy

In proteinuric nephropathies tubular atrophy leads to glomerular-tubule disconnection through an unknown mechanism. Here we studied whether proteinuria promoted glomerular-tubule disconnection in individual nephrons and whether this phenomenon was prevented by an angiotensin-converting enzyme (ACE) inhibitor. Passive Heymann nephritis (PHN) and control rats were studied at 4 and 8 months. Two additional groups of PHN rats received lisinopril (40 mg/L) or a calcium channel blocker (lacidipine, 3 mg/kg) from day 7 after surgery to 8 months. At sacrifice, kidneys were serially sectioned to identify glomerular- tubule abnormalities in individual nephrons and changes in interstitial volume. In PHN rats, the time-dependent increase in proteinuria was paralleled by tubular atrophy leading to glomerular-tubule disconnection and interstitial volume enlargement. Marked apoptosis was invariably found in atrophic tubules in contrast to the absent or very mild terminal dUTP nick-end labeling staining in tubules normally connected to glomeruli in PHN animals. Treatment with an ACE inhibitor prevented hypertension, proteinuria, the formation of atrophic tubuli, glomerular-tubule disconnection and limited the fractional interstitial volume expansion. Although lacidipine limited hypertension, it did not reduce proteinuria or prevent tubular atrophy and disconnection. Multivariate analysis showed that the appearance of atubular glomeruli and the increase in interstitial volume were better predicted by proteinuria than blood pressure. This study suggests that ACE inhibitors effectively prevent glomerular-tubule disconnection possibly by their ability of reducing proteinuria, which in turn favors proximal tubular cell apoptosis. Agents that only reduced hypertension but not proteinuria do not affect tubular behavior.

This article has been cited by other articles:

				J. W. Pippin, P. T. Brinkkoetter, F. C. Cormack-Aboud, R. V. Durvasula, P. V. Hauser, J. Kowalewska, R. D. Krofft, C. M. Logar, C. B. Marshall, T. Ohse, et al. Inducible rodent models of acquired podocyte diseases Am J Physiol Renal Physiol, February 1, 2009; 296(2): F213 - F229. [Abstract] [Full Text] [PDF]

				R. L. Chevalier and M. S. Forbes Generation and Evolution of Atubular Glomeruli in the Progression of Renal Disorders J. Am. Soc. Nephrol., February 1, 2008; 19(2): 197 - 206. [Abstract] [Full Text] [PDF]

				F. Theilig, W. Kriz, T. Jerichow, P. Schrade, B. Hahnel, T. Willnow, M. Le Hir, and S. Bachmann Abrogation of Protein Uptake through Megalin-Deficient Proximal Tubules Does Not Safeguard against Tubulointerstitial Injury J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1824 - 1834. [Abstract] [Full Text] [PDF]

				E. Erkan, P. Devarajan, and G. J. Schwartz Mitochondria Are the Major Targets in Albumin-Induced Apoptosis in Proximal Tubule Cells J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1199 - 1208. [Abstract] [Full Text] [PDF]

				M. S. Forbes, B. A. Thornhill, M. H. Park, and R. L. Chevalier Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury Am. J. Pathol., January 1, 2007; 170(1): 87 - 99. [Abstract] [Full Text] [PDF]

				M. Abbate, C. Zoja, and G. Remuzzi How Does Proteinuria Cause Progressive Renal Damage? J. Am. Soc. Nephrol., November 1, 2006; 17(11): 2974 - 2984. [Abstract] [Full Text] [PDF]

				M. Nangaku, S. J. Shankland, and W. G. Couser Cellular Response to Injury in Membranous Nephropathy J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1195 - 1204. [Abstract] [Full Text] [PDF]

				E. Erkan, C. D. Garcia, L. T. Patterson, J. Mishra, M. M. Mitsnefes, F. J. Kaskel, and P. Devarajan Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis: Roles of Proteinuria and Fas-Dependent Pathways J. Am. Soc. Nephrol., February 1, 2005; 16(2): 398 - 407. [Abstract] [Full Text] [PDF]

				B. Najafian, Y. Kim, J. T. Crosson, and M. Mauer Atubular Glomeruli and Glomerulotubular Junction Abnormalities in Diabetic Nephropathy J. Am. Soc. Nephrol., April 1, 2003; 14(4): 908 - 917. [Abstract] [Full Text] [PDF]

				C. Zoja, D. Corna, D. Camozzi, D. Cattaneo, D. Rottoli, C. Batani, C. Zanchi, M. Abbate, and G. Remuzzi How To Fully Protect the Kidney in a Severe Model of Progressive Nephropathy: A Multidrug Approach J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2898 - 2908. [Abstract] [Full Text] [PDF]