Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model

• Published in: Journal of the American Society of Nephrology Vol. 18; no. 2; pp. 515 - 527
• Main Authors: HIRAMATSU, Noriyuki, HIROMURA, Keiju, UEKI, Kazue, KOPP, Jeffrey B, NOJIMA, Yoshihisa, SHIGEHARA, Tetsuya, KUROIWA, Takashi, IDEURA, Hiroshi, SAKURAI, Noriyuki, TAKEUCHI, Shigeru, TOMIOKA, Mai, IKEUCHI, Hidekazu, KANEKO, Yoriaki
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.02.2007
• Subjects: African Continental Ancestry Group; AIDS-Associated Nephropathy - pathology; AIDS-Associated Nephropathy - prevention & control; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Biological and medical sciences; Disease Models, Animal; Human viral diseases; Humans; Imidazoles - therapeutic use; Infectious diseases; Intracellular Signaling Peptides and Proteins - genetics; Kidney - pathology; Kidney Failure, Chronic - etiology; Kidneys; Medical sciences; Membrane Proteins - genetics; Mice; Mice, Transgenic; Nephrology. Urinary tract diseases; Receptor, Angiotensin, Type 1 - drug effects; Receptor, Angiotensin, Type 1 - physiology; Tetrazoles - therapeutic use; Urinary system involvement in other diseases. Miscellaneous; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Tetrazole derivatives; Nephrology; Olmesartan medoxomil; Urology; Complication; Antagonist; Angiotensin II; Kidney disease; Immunopathology; Urinary system disease; Rodentia; Retroviridae; AIDS; AT1 angiotensin receptor; Immune deficiency; Lentivirus; Infection; Virus; Vertebrata; Mammalia; Nephropathy; Treatment; Mouse; Viral disease; Animal; Angiotensin antagonist; Human immunodeficiency virus
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2006030217

HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.