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.