HIV-associated nephropathy: Role of AT2R

Abstract

AT1R has been reported to play an important role in the progression of HIV-associated nephropathy (HIVAN); however, the effect of AT2R has not been studied. Age and sex matched control (FVB/N) and Tg26 mice aged 4, 8, and 16 weeks were studied for renal tissue expression of AT1R and AT2R (Protocol A). Renal tissue mRNA expression of AT2R was lower in Tg26 mice when compared with control mice. In protocol B, Tg26 mice were treated with either saline, telmisartan (TEL, AT1 blocker), PD123319 (PD, AT2R blocker), or TEL + PD for two weeks. TEL-receiving Tg26 (TRTg) displayed less advanced glomerular and tubular lesions when compared with saline-receiving Tg26 (SRTg). TRTgs displayed enhanced renal tissue AT2R expression when compared to SRTgs. Diminution of renal tissue AT2R expression was associated with advanced renal lesions in SRTgs; whereas, upregulation of AT2R expression in TRTgs was associated with attenuated renal lesions. PD-receiving Tg 26 mice (PDRTg) did not show any alteration in the course of HIVAN; whereas, PD + TEL-receiving Tg26 (PD-TRTg) showed worsening of renal lesions when compared to TRTgs. Interestingly, plasma as well as renal tissues of Tg26 mice displayed several fold higher concentration of Ang III, a ligand of AT2R.

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

“…In brief, human podocytes transfected with plasmid constructs including NL4-3 (pNL4-3: ⌬G/P-EGFP, HIV/CIDHP) and empty vector (EV/CIDHPs) in the presence or absence of VD (EV/VD/CIDHPs or HIV/VD/CIDHPs)/losartan (AT 1 receptor antagonist) were loaded at 37°C for 20 min with Redox Sensor Red CC-1 (1 M) and a mitochondria-specific dye, MitoTracker green FM (50 nM; Molecular Probes) as described previously (40,41).…”

“…Western blot studies. Protein blots of control and experimental cells were prepared as described previously (21,40,41). Nitrocellulose membranes were then processed further for immunostaining with primary antibodies against VDR (Santa Cruz Biotechnology), CTSL (Calbiochem, La Jolla, CA), or renin (Santa Cruz Biotechnology) and subsequently with horseradish peroxidase-labeled appropriate secondary antibodies.…”

“…RT-PCR analysis. Control (EV/CIDHP) and experimental (HIV/ CIDHP) cells were used to quantify mRNA expression of renin and CTSL as described previously (40,41). Quantitative PCR was carried out with the ABI Prism 7900HT sequence detection system using primer sequences as follows: CTSL (NM_001257971.1), forward: 5=-CAGTGAAGAATTCAGG-3=, reverse: 5=-TGCTCACTCAGTG-AGAT-3=; and VDR (NM_000376.2) forward: 5=-GACTTTGACCG-GAACGTGCCC-3=, reverse: 5=-CATCATGCCGATGTCCACACA -3=.…”

“…CTSL has been reported to modulate actin filament reorganization through cleavage of dynamin (41). To determine the effect of HIV on podocyte dynamin expression, EV/CIDHPs and HIV/CIDHPs were colabeled with an anti-dynamin antibody and phalloidin.…”

“…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).…”