title: HIV compromises integrity of the podocyte actin cytoskeleton through downregulation of the vitamin D receptor.
abstract: Alterations in the podocyte actin cytoskeleton have been implicated in the development of proteinuric kidney diseases. In the present study, we evaluated the effect of HIV on the podocyte actin cytoskeleton and the mechanism involved. We hypothesized that HIV may be compromising the actin cytoskeleton via downregulation of the vitamin D receptor (VDR) of conditionally immortalized differentiated human podocytes (CIDHPs). HIV-transduced podocytes (HIV/CIDHPs) not only displayed downregulation of VDR but also showed activation of the renin-angiotensin system (RAS) in the form of enhanced expression of renin and increased production of ANG II. Moreover, CIDHPs lacking VDR displayed enhanced ANG II production, and treatment of HIV/CIDHPs with EB1089 (vitamin D3; VD) attenuated ANG II production. HIV/CIDHPs as well as ANG II-treated CIDHPs exhibited enhanced expression of cathepsin (CTS) L. Additionally, losartan (an ANG II type I receptor blocker) inhibited both HIV- and ANG II-induced podocyte cathepsin L expression. Furthermore, VD downregulated HIV-induced podocyte CTSL expression. Both losartan and free radical scavengers attenuated HIV- and ANG II-induced podocyte reactive oxygen species (ROS) generation. HIV also led to cytosolic CTSL accumulation through enhancement of podocyte lysosomal membrane permeabilization; on the other hand, VD, losartan, and superoxide dismutase (SOD) attenuated HIV-induced enhanced podocyte cytosolic CTSL accumulation. Morphological evaluation of HIV/CIDHPs revealed sparse actin filaments and attenuated expression of dynamin. Interestingly, podocytes lacking CTSL displayed enhanced dynamin expression, and HIV/CIDHPs expressing CTSL exhibited downregulation of dynamin. These findings indicate that HIV-induced downregulation of podocyte VDR and associated RAS activation and cytosolic CTSL accumulation compromised the actin cytoskeleton.
authors: Department of Medicine and Immunology Center, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA.
authors: Nirupama
authors: N
authors: Chandel
authors: Bipin
authors: B
authors: Sharma
authors: Mohammad
authors: M
authors: Husain
authors: Divya
authors: D
authors: Salhan
authors: Tejinder
authors: T
authors: Singh
authors: Partab
authors: P
authors: Rai
authors: Peter W
authors: PW
authors: Mathieson
authors: Moin A
authors: MA
authors: Saleem
authors: Ashwani
authors: A
authors: Malhotra
authors: Pravin C
authors: PC
authors: Singhal
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000821:virology; D000199:Actins; D000804:Angiotensin II / Q000096:biosynthesis; D056668:Cathepsin L / Q000235:genetics; D003599:Cytoskeleton / Q000648:ultrastructure*; D015536:Down-Regulation; D015870:Gene Expression; D015658:HIV Infections / Q000473:pathology / Q000503:physiopathology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018384:Oxidative Stress; D050199:Podocytes / Q000648:ultrastructure / Q000821:virology*; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D000199:Actins; D018167:Receptors, Calcitriol; D000804:Angiotensin II; D056668:Cathepsin L
keywords: HIV-associated nephropathy; cathepsin L; podocyte; renin-angiotensin system; vitamin D receptor