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J Am Soc Nephrol 12:941-948, 2001
© 2001 American Society of Nephrology

Blocking Angiotensin II Synthesis/Activity Preserves Glomerular Nephrin in Rats with Severe Nephrosis

ARIELA BENIGNI*, SUSANNA TOMASONI*, ELENA GAGLIARDINI*, CARLA ZOJA*, JAMES A. GRUNKEMEYER{ddagger}, RAGHU KALLURI{ddagger} and GIUSEPPE REMUZZI*,{dagger}

* Mario Negri Institute Bergamo, Italy
{dagger} Ospedali Riuniti di Bergamo, Azienda Ospedaliera, Bergamo, Italy
{ddagger} Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.

Correspondence to Dr. Ariela Benigni, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: 39-035-319-888; Fax: 39-035-319-331; E-mail: abenigni{at}marionegri.it

Abstract. Angiotensin-converting enzyme inhibitors restore size-selective dysfunction of the glomerular barrier in experimental animals and humans with proteinuric nephropathies, although the structural and molecular determinants of such an effect are not completely understood. This study used an accelerated model of experimental nephrosis to assess nephrin gene and protein expression in the kidney and the possible modulating effect of drugs that block angiotensin II (AII) synthesis/activity. Passive Heymann nephritis (PHN) and control animals were studied at day 7, month 4, and month 8. Additional PHN rats were treated with lisinopril or AII receptor blocker L-158,809 and studied at 8 mo. Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury. An intense signal of nephrin mRNA was detected in glomeruli of control animals mainly restricted to podocytes. In PHN rats, nephrin staining progressively and remarkably decreased with time. Lisinopril and L-158,809 fully prevented the decrease in nephrin transcripts to levels comparable to those of control rats. Consistent with nephrin mRNA expression, immunostaining of the protein showed a progressive decrease in kidneys from PHN rats that was completely abolished by lisinopril and L-158,809. In summary, progressive renal injury was associated with downregulation of nephrin gene that was totally prevented by angiotensin-converting enzyme inhibitor and AII receptor blocker, suggesting that renoprotection afforded by drugs that interfere with AII synthesis/activity was related to an effect on nephrin assembly.




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