Angiotensin II Type 1 Receptor Blockade Inhibits the Development and Progression of HIV-Associated Nephropathy in a Mouse Model

Abstract

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. Nephroticrange 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.

Transgenic and Infectious Animal Models of HIV-Associated Nephropathy

“…49,50 More recently, the angiotensin II type 1 receptor blocker olmesartan also reduced disease in the inducible podocyte-specific Vpr murine HIVAN model. 47 Conversely, administration of angiotensin II in this same model exacerbated progression of the disease. 51 This effect was independent of angiotensin II or olmesartan's effect on systemic BP because other vasoactive agents (norepinephrine, hydralazine, and azelnidipine) did not have an effect on renal pathology.…”

“…Podocyte-specific expression of the single HIV genes Vif, Tat, Vpu, and Rev resulted in no renal injury. 46 A doxycycline-inducible podocyte-specific Vpr transgenic model that used the podocin promoter also showed HIVAN pathology 16 wk after induction (see Hiramatsu et al 47 in Table 1). This system more accurately reflects a natural HIV infection because Vpr expression is restricted until adulthood and further validates the results from noninducible models.…”

Angiotensin II Infusion Induces Nephrin Expression Changes and Podocyte Apoptosis

“…Its infusion has been shown to accelerate renal fibrosis in a mouse model of HIV-1-associated nephropathy [9]. On the other hand, its blockade of action or production has also been shown to result in diminution of proteinuria as well as slowing down of the progression of renal fibrosis in mice transgenic for HIV-1 [10, 11]. Similar results have been demonstrated in rat models of diabetes and hypertension [12, 13].…”

Proteomic analysis identifies insulin-like growth factor-binding protein-related protein-1 as a podocyte product

“…A recent report showed that oncogenic activation in human fibroblasts and melanocytes leads to synthesis of IGFBP-rP1 and induces senescence and apoptosis in an autocrine/paracrine manner (32). The Vpr-transgenic mouse represents podocyte dysregulation and apoptosis after doxycycline administration (11). It is possible that podocyte dysregulation by the Vpr gene may lead to IGFBP-rP1 secretion.…”