Adverse Host Factors Exacerbate Occult HIV-Associated Nephropathy

Abstract

In the present study, we hypothesized that HIV-1-induced occult HIV-associated nephropathy (HIVAN) would become apparent in the presence of adverse host factors. To test our hypothesis, Vpr mice (which display doxycycline-dependent Vpr expression in podocytes) with two, three, and four copies of the angiotensinogen (Agt) gene (Vpr-Agt-2, Vpr-Agt-3, and Vpr-Agt-4) were administered doxycycline for 3 weeks (to develop clinically occult HIVAN) followed by doxycycline-free water during the next 3 weeks. Subsequently, renal biomarkers were measured, and kidneys were harvested for renal histology. Vpr-Agt-2 developed neither proteinuria nor elevated blood pressure, and displayed minimal glomerular and tubular lesions only, without any microcyst formation. Vpr-Agt-3 showed mild glomerular and tubular lesions and microcyst formation, whereas Vpr-Agt-4 showed moderate proteinuria, hypertension, glomerular sclerosis, tubular dilation, microcysts, and expression of epithelial mesenchymal transition markers. Vpr-Agt-4 not only displayed enhanced renal tissue expression of Agt, renin, and angiotensin-converting enzyme, but also had higher renal tissue concentrations of angiotensin II. Moreover, renal cells in Vpr-Agt-4 showed enhanced expression of transforming growth factor-β, connective tissue growth factor, and vascular endothelial growth factor. These findings indicate that adverse host factors, such as the activation of the renin-angiotensin system, promote the progression of occult HIVAN to apparent HIVAN.

HIV compromises integrity of the podocyte actin cytoskeleton through downregulation of the vitamin D receptor

“…Local ANG II production has the potential to modulate kidney homeostasis in multiple ways, including alteration of kidney cell expression of cytokines, influx of immune cells, synthesis of extracellular matrix components, and cell growth. In a recent report, enhanced renal tissue production of ANG II accelerated clinically occult HIVAN into an overt HIVAN (26). In the present study, HIV directly enhanced the activation of the RAS in podocytes.…”

“…Moreover, infusion of ANG II accelerated the progression of HIVAN in a mouse model (22). In a recent report, increased copies of angiotensinogen exacerbated occult HIVAN to overt HIVAN in a genetically engineered mouse model of HIVAN (26). All of these reports confirm the role of the RAS in the progression of HIVAN.…”

“…Local RAS has been implicated to play an important role in the induction as well as progression of kidney cell injury in several kidney disease models (24,26,30,33). Local ANG II production has the potential to modulate kidney homeostasis in multiple ways, including alteration of kidney cell expression of cytokines, influx of immune cells, synthesis of extracellular matrix components, and cell growth.…”

“…THE RENIN-ANGIOTENSIN SYSTEM (RAS) has been demonstrated to play a key role in the progression of kidney disease in general and HIV-associated nephropathy (HIVAN) in particular (1,6,14,16,26,30,31,41,44). Modalities, which are known to inhibit the production or block the effect of ANG II on kidney cells, have been reported to slow down the progression of renal lesions in both human and experimental animal models of HIVAN (4,5).…”

Inhibition of renin activity slows down the progression of HIV-associated nephropathy

“…The Vpr mouse model is well characterized and has been used in multiple studies to explore the mechanisms involved in HIVAN (9,15,19,20,24,34). We (22) have recently described the detailed morphology and characteristics of renal lesions in this model. These mice do not have any specific phenotype and develop renal lesions only after ingestion of Doxy.…”