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Progressive Glomerulosclerosis and Enhanced Renal Accumulation Of Proc. Natl. Acad. Sci. USA Vol. 89, pp. 1577-1581, March 1992 Medical Sciences Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes JEFFREY B. KOPP*t, MARY E. KLOTMANt, SCOTT H. ADLER*, LESLIE A. BRUGGEMAN*, PETER DICKIE§, NANCY J. MARINOS§, MICHAEL ECKHAUS¶, JOSEPH L. BRYANT"1, ABNER L. NOTKINS§, AND PAUL E. KLOTMAN* *Laboratory of Developmental Biology, §Laboratory of Oral Medicine, and I1Animal Care Unit, National Institute of Dental Research, *Laboratory of Tumor Cell Biology, National Cancer Institute, and WVeterinary Resources Program, National Center for Research Resources, National Institutes of Health, Bethesda, MD 20892 Communicated by Marilyn G. Farquhar, November 5, 1991 ABSTRACT Patients infected with human immunodefi- MATERIALS AND METHODS charac- ciency virus type 1 (HIV-1) develop a renal syndrome Transgenic Mice. The transgene, 7.4 kb long, consisted of terized by proteinuria, renal failure, and focal segmental the proviral HIV genome, lacking 3 kb of sequence overlap- glomerulosclerosis. By using a noninfectious HIV-1 DNA con- ping the gag and pol genes. The remaining proviral sequence struct lacking the gag and pol genes, three transgenic mouse included the 5' and 3' long terminal repeats (LTRs) and the lines have been generated that develop a syndrome remarkably env, tat, nef, rev, vif, vpr, and vpu genes (8). The transgene similar to the human disease. In the present study, we have was introduced into male pronuclei of FVB/N mouse characterized in detail one of these lines, Tg26. In Tg26 mice, oocytes, resulting in nine founder animals, all of which proteinuria was detectable at -24 days of age, followed by remained healthy. Male founder mice were back-crossed severe nephrotic syndrome and rapid progression to end-stage with normal female FVB/N mice to produce the F1 genera- renal failure. Renal histology showed focal segmental glomer- tion. Three of the eight male founder animals (Tg22, Tg25, ulosclerosis and microcystic tubular dilatation. Indirect immu- and Tg26) gave rise to lines that developed progressive renal nofluorescence studies demonstrated increased accumulation disease in the F1 generation, and all three of these founders of the basement membrane components laminin, collagen type had unique restriction fragment length polymorphisms for the IV, and heparan sulfate proteoglycan. The viral protein Rev transgene (9). was present in sclerotic glomeruli. Northern blot analysis of Southern Blot Analysis. Ten micrograms of tail DNA was total renal RNA showed expression of viral genes prior to the digested with EcoRI, electrophoresed through 0.7% agarose appearance of histologic renal disease, with greatly diminished gels, and transferred to nylon membranes. DNA was probed viral gene expression late in the disease course. Kidneys from with a cDNA encoding the HIV-1 nefgene (10) radioactively transgenic mice expressed increased steady-state levels of col- labeled using [32P]dCTP (New England Nuclear/DuPont) by lagen al(IV) mRNA when glomerulosclerosis was present. We the random-primer method (Boehringer Mannheim). Hybrid- conclude that the presence of HIV-1 genes is associated with ization was carried out at 37°C in 50% (vol/vol) formamide/ progressive renal dysfunction and glomerulosclerosis in trans- dextran sulfate (0.1 g/ml)/5x SSPE/10 mM Tris-HCI, pH genic mice. 7.5/4x Denhardt's solution/denatured salmon sperm DNA (0.1 mg/ml). (1x SSPE = 0.18 M NaCI/10 mM sodium Among the protean manifestations now recognized as se- phosphate, pH 7.4/1 mM EDTA.) The filters were washed quelae of infection with human immunodeficiency virus type under highly stringent conditions at 68°C in 0.1x standard 1 (HIV-1) is a renal syndrome, termed HIV-associated saline citrate (SSC)/0.1% SDS and autoradiographic expo- nephropathy. This syndrome is characterized clinically by sures were made at -70°C. heavy proteinuria, often with the nephrotic syndrome, and a Serum and Urine Chemistry. Blood (200 ,ul) was obtained high incidence of progression to end-stage renal disease by retroorbital puncture at 20-day intervals. Blood urea (1-6). Pathologically, the most common glomerular lesions in nitrogen, serum cholesterol, and serum albumin were as- HIV-associated nephropathy are focal segmental glomerulo- sayed using commercially available kits (Boehringer Mann- of the heim). Urine protein was measured with a colorometric assay sclerosis and microcystic tubular dilatation (6). Some using pyrogallol red/molybdate (Biotrol USA, West Chester, remaining patients have mesangial proliferation (7). PA), and urine creatinine was measured by the picric acid Recently, we developed transgenic mouse lines that bear method. HIV-1 genes. A defective form of the HIV-1 provirus that Histology. Zinc formalin-fixed paraffin-embedded renal lacks 3 kilobases (kb) of sequence overlapping the gag and sections were cut at 3 ,um and stained with periodic acid/ pol sequences was introduced into mice as a transgene. Schiff reagent (PAS) or Yajima silver. Renal tissue was Transgenic lines derived from three founder animals devel- embedded in OCT compound (Tissue-Tek; Miles) and frozen oped proteinuria, progressive renal failure, glomeruloscler- in isopentane at -70°C. Sections (4 gm) were cut, air-dried osis, and microcystic tubular dilatation. In the present study, overnight at room temperature, and fixed in acetone at 4°C. we describe in detail the clinical, pathological, and molecular Sections were blocked with normal goat serum diluted 1:5 in biological manifestations of the renal disease in one of these phosphate-buffered saline (PBS) and exposed to fluoresce- transgenic mouse lines (Tg26). Abbreviations: HIV-1, human immunodeficiency virus type 1; LTR, long terminal repeat; PAS, periodic acid/Schiff reagent. The publication costs of this article were defrayed in part by page charge tTo whom reprint requests should be addressed at: Building 30, payment. This article must therefore be hereby marked "advertisement" Room 430, National Institute of Dental Research, National Insti- in accordance with 18 U.S.C. §1734 solely to indicate this fact. tutes of Health, Bethesda, MD 20892. 1577 Downloaded by guest on September 29, 2021 1578 Medical Sciences: Kopp et al. Proc. NaM Acad Sci. USA 89 (1992) inated primary antibody diluted 1:40 in PBS for 60 min at A room temperature. Affinity-purified primary antibody in- cluded goat anti-mouse IgG, goat anti-mouse IgM, goat anti-mouse IgA (Kirkegaard and Perry Laboratories, Gaith- ersburg, MD), and sheep anti-mouse complement (Biodesign International, Kennebunkport, ME). Immunohistology for Extracellular Matrix and Viral Pro- teins. Paraffin sections (4 Mum) were deparaffinized and di- gested with 0.5% trypsin for 60 min at 370C. Sections were _ blocked with normal goat serum, exposed to specific anti- body diluted 1:40 in PBS for 60 min, and washed with PBS. k _ Affinity-purified fluoresceinated goat anti-rabbit antibody (Kirkegaard and Perry), diluted 1:40 in PBS, was applied for 60 min. The specific rabbit antisera used included anti-mouse laminin and anti-mouse collagen type IV (kindly provided by Hynda Kleinman, National Institute of Dental Research), anti-mouse basement membrane heparan sulfate proteogly- can core protein (11), and antiserum directed against residues 26-51 of Rev. Extraction ofTotal RNA and Northern Blot Analysis. Mouse kidneys were snap frozen in liquid nitrogen and total renal RNA was isolated by centrifugation through cesium chloride (12). RNA (10,Mg) was electrophoresed through 1% agarose/ formaldehyde gels, transferred to nylon filters, and fixed by baking for 2 hr at 80'C. The following cDNA probes were 32P-labeled using the random-primer method: a 1.2-kb Hind- FIG. 1. Normal, heterozygous, and homozygous HIV-transgenic III fragment of nef cDNA (10), a 1.5-kb EcoRI-HindIII mice. (A) Breeding of heterozygous F1 generation transgenic mice fragment from mouse laminin B2 chain cDNA (13), a 0.8-kb from line Tg26 produced offspring with three genotypes, shown here Pst I-Ava I fragment of mouse collagen al(IV) cDNA (14), at 14 days of age: transgenic homozygous mice that were runted at the time of birth and generally died by age 30 days (Left), transgenic and a human ribosomal S14 protein cDNA (American Type heterozygous mice that were phenotypicaily normal at this age Culture Collection 59246). Hybridization was carried out at (Center), and normal nontransgenic homozygous mice (Right). (B) 37°C in 50% formamide/dextran sulfate (0.1 g/ml)/5x Southern blot analysis was performed with tail DNA, cut with SSC/10 mM Tris-HCI, pH 7.5/4x Denhardt's solution/ EcoRI, and probed with a cDNA encoding the nefgene. DNA from denatured salmon sperm DNA (0.1 mg/ml). The filters were the transgenic homozygous mouse (lane 1) exhibited both a dominant washed at 55°C in 0.1x SSC/0.1% SDS. Autoradiographic 7-kb band (arrow) and fainter higher molecular weight bands (bars). exposures were made at -70°C, and the blots were scanned DNA obtained from heterozygous animals had -5PO% of the hybrid- on a Phosphoimager (Molecular Dynamics, Sunnyvale, CA), ization intensity as that of homozygous littermates (lane 2). Normal which provided a direct measure of radioactivity. nontransgenic mouse DNA is indicated in lane 3. Statistics. Data are expressed as mean ± standard devia- tion. Student's t test was performed using the StatView II of the nephrotic syndrome. In seven normal mice, serum statistical package (Abacus Concepts, Berkeley, CA). albumin was 3.5 ±f 0.5 g/dl and serum cholesterol was 143 ± 26 mg/dl, whereas in seven age-matched transgenic mice with edema, serum albumin was 2.4 ± 0.5 g/dl (P < 0.01) and RESULTS serum cholesterol was 387 ± 148 mg/dl (P < 0.001). Death F1 offspring from the Tg26 founder were mated and the from uremia occurred within 10-15 days of the onset of resulting litters contained nontransgenic homozygous (nor- edema.
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