title: Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN.
abstract: HIV-associated nephropathy (HIVAN) is a common complication of HIV-1 infection in patients with African ancestry in general and with APOL1 gene risk variants in particular. Although collapsing glomerulopathy is considered a hallmark of HIVAN, significant numbers of glomeruli in patients with HIVAN also display other variants of focal segmental glomerulosclerosis (FSGS). We propose that collapsed glomeruli as well as glomeruli with other variants of FSGS are manifestations of HIVAN and their prevalence depends on associated host factors. We explored the role of the renin-angiotensin system (RAS) in the manifestation of any specific glomerular phenotype in HIVAN. To evaluate the role of the RAS we have used a genetically engineered mouse model of HIVAN (Tg26) with two and four copies of angiotensinogen (Agt) gene (Tg26/Agt2 and Tg26/Agt4). In Tg26/Agt2, 1 out of 6 glomeruli exhibited sclerosed phenotype, whereas 1 out of 25 glomeruli displayed collapsed phenotype; on the other hand, in Tg26/Agt4, 1 out of 3 glomeruli exhibited sclerotic phenotype and only 1 out of 7 glomeruli showed collapsed phenotype. To inhibit the effect of RAS, Tg26/Agt2 were administered captopril, aliskiren, aliskiren plus captopril or aliskiren plus telmisartan by miniosmotic pumps for 4 weeks. In all experimental groups there was a significant reduction in percentage of sclerosed glomeruli and only minimal reduction in collapsed glomeruli compared to normal saline receiving Tg26/Agt2. These findings suggest that the manifestation of the sclerosed phenotype in HIVAN is predominantly dependent on activation of the RAS.
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Plagov
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Lan
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Partab
authors.initials: P
authors.lastname: Rai
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Rivka
authors.initials: R
authors.lastname: Lederman
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Shabina
authors.initials: S
authors.lastname: Rehman
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Ding
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY, USA.
authors.forename: Praveen N
authors.initials: PN
authors.lastname: Chander
authors.affiliation: Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Manhasset, NY, USA. psinghal@nshs.edu.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012084:Renin-Angiotensin System / Q000235:genetics*