Microcyst Formation and HIV-1 Gene Expression Occur in Multiple Nephron Segments in HIV-Associated Nephropathy
Michael J. Ross,
Leslie A. Bruggeman,
Patricia D. Wilson and
Paul E. Klotman
Dr. Bruggeman’s current affiliation: Rammelkamp Center for Research and Education, Case Western Reserve University, Cleveland, Ohio.
Division of NephrologyMount Sinai School of Medicine, New York, New York.
Correspondence to Dr. Michael J. Ross, One Gustave L. Levy Place, Box 1243, New York, NY 10029. Phone: 212-241-0131; Fax: 212-987-0389; E-mail: michael.ross{at}mssm.edu
ABSTRACT. Tubular microcyst formation is a prominent histopathologicfeature of HIV-associated nephropathy (HIVAN), but its pathogenesisis unknown. HIV-1 has recently been shown to infect renal tubularepithelial cells in patients with HIVAN. In addition, HIV-1gene expression in renal epithelial cells has been shown tocause a renal disease that is identical to HIVAN in HIV-1 transgenicmice. In these studies, immunohistochemistry for tubular segment-specificmarkers and mRNA in situ hybridization for HIV-1 was used todetermine which tubular segments develop microcysts and whichsegments express HIV-1 in the kidneys of transgenic mice andpatients with HIVAN. It was found that microcysts involve multiplenephron segments in both patients with HIVAN and HIV-1 transgenicmice. Furthermore, HIV-1 infection in HIVAN and HIV-1 transgeneexpression also occurs in multiple segments of the nephron.These data support a direct role for HIV-1 infection of renalepithelial cells in the pathogenesis of microcyst formationin patients with HIVAN.
HIV-associated nephropathy (HIVAN) is the third most commoncause of end-stage renal disease (ESRD) in African Americansaged 20 to 64 yr. It is also the most common cause of ESRD inHIV-1 seropositive individuals (1). HIVAN occurs almost exclusivelyin African Americans and is typically diagnosed late in thecourse of HIV-1 infection (2,3), although earlier cases areincreasingly being recognized (4,5). Before the introductionof highly active antiretroviral therapy, renal prognosis waspoor, with most patients progressing to ESRD within 4 mo (2).The diagnosis of HIVAN cannot be made by clinical criteria aloneand requires a renal biopsy. Diagnostic changes upon histologicexamination of the biopsy include focal segmental glomerulosclerosis,usually of the collapsing variant, combined with microcysticdilation of tubules (Figure 1A) (6–8). Other tubular abnormalitiesobserved in HIVAN include tubular atrophy, tubular epithelialsimplification, loss of brush border, and proximal tubular proteinand lipid resorption droplets (7).
Figure 1. Histologic appearance of tubular microcysts in HIV-associated nephropathy (HIVAN) occurring in humans and HIV-1 transgenic mice. (A) Biopsy of renal cortex from patient with HIVAN demonstrating cystic dilation of tubules. (B) Renal cortex of HIV-1 transgenic mouse. Microcystic dilation of tubules is similar to that seen in human HIVAN. Magnifications: x100 in A; x200 in B.
The pathogenesis of microcyst formation in HIVAN remains poorlyunderstood. Microcysts are dilated tubules that have at leastthree times the external diameter of normal tubules. We havereported previously that renal tubular epithelial cells areinfected by HIV-1 in HIVAN (9). We have also demonstrated thatHIV-1 gene transcription ceases as tubules dilate and the epitheliumbecomes flattened and atrophic (10). The nephron segments thatbecome infected by HIV-1 and develop microcysts in HIVAN, however,remain unknown. If HIV-1 infection and microcyst formation werefound to occur in the same tubular distribution, this wouldprovide suggestive evidence for a direct etiologic role forHIV-1 infection in the formation of renal tubular microcysts.
In this study, we have used immunohistochemistry for tubularsegment-specific markers and mRNA in situ hybridization forHIV-1 to identify the specific segments involved in microcystictubular disease in HIVAN. We show that in both human HIVAN andthe HIV-1 transgenic mouse model, HIV-1 expression and microcystformation involve multiple nephron segments and that the distributionof HIV-1 expression and microcyst formation are similar.
Human and Murine Kidney Tissue
The development of the transgenic mouse line TgN(pNL43 d14)26Lhas been reported previously (11,12). The proviral transgene,pNL4-3:d1443, encodes all HIV-1 genes except gag and pol. Theprovirus is replication-defective, and the mice are noninfectious;however, heterozygotes develop proteinuria, renal failure, andrenal disease that is histologically identical to HIVAN in humans.Homozygous mice develop a wasting phenotype and seldom surviveto weaning (13,14). This murine model of HIVAN has been characterizedextensively (11,12,15). The distribution of HIV-1 transgeneexpression has been previously shown to be highest in skin,tail, and muscle, with lower levels present in kidney and intestineand little expression in liver as detected by Northern blotanalysis (16). Transgene expression is detectable by in situhybridization in several renal epithelial cell types (glomerularvisceral and parietal epithelial cells and tubular epithelialcells) but not in mesangial or endothelial cells (15).
All studies using mice were approved by the Institutional AnimalCare and Use Committee of Mount Sinai School of Medicine.
Human biopsy material was collected previously from patientswith HIVAN after informed consent under a protocol approvedby the Mount Sinai Institutional Review Board.
Human (n = 6) and normal (n = 4) and transgenic (n = 4) mousekidney tissue was fixed in 4% paraformaldehyde at 4°C for2 to 4 h. Tissue was embedded in paraffin and stored at -80°Cto prevent RNA degradation.
Light Microscopy and Alkaline Phosphatase Staining
Paraffin-embedded sections were dewaxed and rehydrated in aseries of graded ethanols. Slides were stained with periodicacid-Schiff or hematoxylin and eosin. Endogenous alkaline phophatasewas detected by incubation in 0.3 mM 4-nitro blue tetrazoliumchloride and 0.3 mM 5-bromo-4-chloro-3-indolyl-phosphate in0.2 mM Tris buffer (pH 9.5) for 5 to 10 min.
Immunohistochemistry
Paraffin-embedded tissue sections (5 µm) were placed ontoSuperfrost Plus slides (VWR Scientific, West Chester, PA). Slideswere dewaxed in xylene and rehydrated in a graded series ofethanols. Slides were then incubated in aqueous 7.5% H2O2 toblock endogenous peroxidase activity. Slides were then incubatedin 2% normal goat or rabbit serum in phosphate-buffered saline(PBS) at room temperature for 40 min. Slides were then incubatedfor 45 min with one of the following primary antibodies anddilutions: rabbit anti-rat aquaporin-1 (AQP-1), 1:500 (AlphaDiagnostic, San Antonio, TX); rabbit anti-rat AQP-2, 1:50 (AlphaDiagnostic); goat anti-human Tamm-Horsfall glycoprotein, 1:1500(Cappel Pharmaceuticals, Aurora, OH); or rabbit anti-mouse epidermalgrowth factor (EGF), 1:200 (Upstate Biotechnology, Lake Placid,NY). Primary antibodies were diluted in PBS containing 2% bovineserum albumin and 2% normal serum from the secondary antibodyspecies. After incubation, slides were washed twice in PBS-0.1%Tween 20 and once in PBS for 5 min each. Slides were then incubatedwith one of the following biotinylated secondary antibodies:goat anti-rabbit IgG (Vector Laboratories, Burlington, CA) orrabbit anti-goat (Pierce, Rockford, IL). Slides were then washedtwice in PBS-0.1% Tween 20 and once in PBS and then incubatedfor 45 min with avidin-peroxidase (Vectastain elite, VectorLaboratories). Slides were washed once in PBS and twice in Tris-bufferedsaline for 5 min each. Color development was accomplished byincubating slides with aminoethylcarbazole for 10 to 30 minfollowed by three 5-min rinses in water. Slides were then counterstainedwith hematoxylin (Vector Laboratories), rinsed three times inwater for 2 min, mounted in Aqua Poly/Mount (Polysciences, Warrington,PA), and photographed under an Olympus BX60 microscope (Olympus,Tokyo, Japan).
In Situ Hybridization
Paraffin sections (5 µm) from mouse and human renal tissuewere placed onto poly-L-lysine-coated slides and dried for 2h at 42°C. In situ hybridization using digoxigenin-labeledriboprobes was performed as described previously (17).
For in situ hybridization in HIV-1 transgenic mice, riboprobesto HIV-1 nef were generated as described previously (15) fromplasmids pGM92 and pGM93 (NIH AIDS Research and Reference ReagentProgram). These plasmids contain 1.1 kb of the HxB2 HIV-1 nefcoding region in opposite orientations to generate sense andantisense riboprobes. The 1.1-kb riboprobes were randomly cleavedwith alkali to an average length of less than 500 bp to enhancetissue penetration.
For in situ hybridization in human tissue, sense and antisenseriboprobes to HIV-1 gag were generated from a 359-bp PCR fragmentfrom HxB2 (nt 1031–1390) subcloned into pGEM-T Easy (Promega,Madison, WI).
Tubulointerstitial Disease in HIVAN and HIV-1 Transgenic Mice
Tubular microcysts are prominent histologic features of HIVANand the renal disease in HIV-1 transgenic mice (Figure 1). Themorphology of the tubular microcysts is similar in HIVAN (Figure 1A)and HIV-1 transgenic mice (Figure 1B).
Localization of Microcysts in HIV-1 Transgenic Mice
To determine which tubular segments develop microcysts, we immunostainedkidneys from HIV-1 transgenic mice for tubule segment-specificantigens (Table 1). We chose this method instead of lectin stainingbecause the carbohydrate moieties on the surface of renal epithelialcells to which lectins bind may be altered in the presence oftubular disease (18). Devuyst et al. (19) reported that AQP-1and AQP-2 retain their tubular segment-specific expression inautosomal dominant polycystic kidney disease (ADPKD) even intoend-stage disease. Alkaline phosphatase (20), EGF (21,22), andTamm-Horsfall protein (23,24) expression have also been characterizedin normal kidneys and in cystic renal diseases.
Table 1. Antigens used to identify specific nephron segments
Microcysts were found in proximal tubules (positive for alkalinephosphatase; Figure 2, B and C), thin descending limb (positivefor AQP-1; Figure 2, E and F), thick ascending limb (positivefor Tamm-Horsfall protein and EGF; Figure 2, H, I, K, and L),and collecting duct (positive for AQP-2; Figure 2, N, O, Q, and R).Cystic proximal tubules were also detected by AQP-1staining (data not shown). Individual microcysts did not expressmore than one of these proteins when serial sections were examined(data not shown).
Figure 2. Microcysts involve all tubular segments in HIV-1 transgenic mice. Immunohistochemistry was performed on kidneys from normal mice (left column) and HIV-1 transgenic mice (middle and right columns) using the following tubule segment-specific markers: alkaline phosphatase (Alk phos), aquaporin-1 (AQP-1), Tamm-Horsfall protein, epidermal growth factor (EGF), and aquaporin-2 (AQP-2). Photographic enlargement of tubules from center column are shown in right column. Magnifications: x200 in A through D); x400 in E through R.
Localization of Microcysts in Patients with HIVAN
Immunostaining for tubule segment-specific markers was performedin renal biopsy specimens from patients with HIVAN (Figure 3).Microcysts were found in proximal tubules (positive for AQP-1;Figure 3, A and B), thick ascending limb (positive for Tamm-Horsfallprotein; Figure 3, C and D), and collecting duct (positive forAQP-2; Figure 3, E and F). Thus, in HIV-1 transgenic mice andpatients with HIVAN, tubular microcysts develop in multiplenephron segments. Interestingly, Tamm-Horsfall staining, whenpresent, was often heterogeneous within microcystic tubules.Despite the heterogeneous expression of Tamm-Horsfall protein,however, HIV-1 expression in cells lining these tubules washomogeneous (data not shown).
Figure 3. Patients with HIVAN develop tubular microcysts in the same tubular distribution as HIV-1 transgenic mice. (A) A microcystic proximal tubule expressing AQP-1 is shown. (B) Photographic enlargement of the same tubule reveals apical and basolateral localization of aquaporin-1. (C) A microcyst involving the thick ascending limb (positive for Tamm-Horsfall protein). (D) Photographic enlargement of C. Note that not all cells along the tubule stain for Tamm-Horsfall protein. (E) A microcystic collecting duct expressing AQP-2. (F) Photographic enlargement of the same tubule demonstrates apical localization of AQP-2. Magnifications: x400 in A, C, E.
Localization of HIV-1 mRNA in Transgenic Mice and HIVAN Biopsies
In HIV-1 transgenic mice, mRNA in situ hybridization using anantisense riboprobe to HIV-1 nef revealed expression of HIV-1mRNA throughout the kidney (Figure 4). As microcysts expandand the tubular epithelium becomes atrophic, expression of theHIV-1 transgene decreased (10).
Figure 4. HIV-1 transgene expression occurs in tubular epithelia throughout kidneys in HIV-1 transgenic mice. (A) In situ hybridization using HIV-1 nef sense control riboprobe demonstrated no specific staining. However, in situ hybridization with an HIV-1 nef antisense riboprobe (B) revealed staining in tubular epithelia from all regions of the kidney. Magnification, x100
In patients with HIVAN, HIV-1 expression by in situ hybridizationwas also determined. HIV-1 was detected in several, but notall, of the tubules that were examined (Figure 5). Colocalizationof HIV-1 mRNA was performed by immunostaining serial sectionsfor tubule segment-specific markers (Figure 5). HIV-1 mRNA colocalizedwith markers for proximal tubules (positive for AQP-1; Figure 5, A through C),thick ascending limb (positive for Tamm-Horsfallprotein; Figure 5, D through F), and collecting duct (positivefor AQP-2; Figure 5, G through I). HIV-1 expression was alsodetected in podocytes (Figure 5E) and interstitial leukocytes(Figure 5I), as has been previously reported (15). Thus, inboth the murine model of HIVAN and in patients with HIVAN, HIV-1gene expression occurred in multiple nephron segments. Epithelialcells lining severely dilated tubules were negative for HIV-1expression; however, mildly dilated tubules were often positivefor HIV-1 as seen in Figure 5, A through C.
Figure 5. In patients with HIVAN, HIV-1 gene expression occurs in tubular epithelia of multiple nephron segments. In situ hybridization was performed using HIV-1 gag sense and antisense riboprobes. Colocalization with tubule segment-specific markers was performed by immunostaining serial sections. HIV-1 gag mRNA (B, E, and H) colocalized with AQP-1 in proximal tubule (A), Tamm-Horsfall protein in thick ascending limb (D), and AQP-2 in collecting duct (G). Panels C, F, and I are photographic enlargements of tubules from B, E, and H respectively. Gag sense control is shown in panel J. Magnification, x400 in all panels.
Studies involving HIV-1 transgenic mice have been valuable inadvancing our understanding of the pathogenesis of HIVAN. Inthis murine model of HIVAN, renal expression of HIV-1 is necessaryfor the development of HIVAN (15). Similarly, in patients withHIVAN, HIV-1 infects and is expressed in renal epithelial cells(9). The segments of the renal tubule that both develop microcystsand are infected by HIV-1 have remained unclear.
In the present studies, we have shown that microcyst formationoccurs in multiple nephron segments in both HIV-1 transgenicmice and in HIVAN biopsy samples. In cystic diseases, such asADPKD, cysts are derived from all nephron segments (25,26),and in autosomal recessive polycystic kidney disease (ARPKD),cysts are derived predominantly from collecting duct (27). Thus,the distribution of microcyst formation in HIVAN most closelyresembles that in ADPKD. This finding also suggests that HIV-1can infect epithelial cells from all nephron segments.
In ADPKD and ARPKD, tubular epithelial cell proliferation isa key element in the pathogenesis of cyst formation (22,28–30).In HIVAN, increased proliferation occurs in both podocytes andtubular epithelial cells (31). HIV-1 gene expression has beenshown to be associated with increased epithelial cell proliferationin HIV-1 transgenic mice (15). In HIV-1 transgenic mice, allnormal and proliferating tubular epithelial cells express theHIV-1 transgene. When the epithelium of microcysts becomes flattenedand atrophic late in the disease process, however, transgeneexpression ceases (10). These findings suggest that renal epithelialHIV-1 gene expression induces epithelial proliferation. Thistemporal relationship in which HIV-1 gene expression is greatestin relatively normal appearing host cells but is lost as microcystsdevelop may explain why microcysts do not evolve into macrocystsin HIVAN. In addition, the tubular distribution of HIV-1 expressionwas demonstrated to be similar to the distribution of microcystsin that multiple nephron segments are involved in each case.These findings are consistent with the hypothesis that HIV-1expression has a direct role in microcyst formation.
In ADPKD, renal epithelial cells lose some characteristics ofmature renal tubular cells such as basolateral polarizationof the Na,K-ATPase and the epidermal growth factor receptor(17,22,28,32,33). ADPKD tubular cells, however, retain normalexpression of other proteins, such as AQP-1 and AQP-2, eveninto end-stage disease. Similarly, in HIVAN, although Na,K-ATPaseexpression may be altered (10), proteins, such as AQP-1 andAQP-2, retain their normal patterns of expression. In HIVAN,Tamm-Horsfall protein expression occurs in its normal location,the thick ascending limb of Henle; however, expression ceasesin some cells lining microcystic tubules. This may reflect changesin cellular differentiation induced by HIV-1 infection. Thus,in HIVAN as tubules dilate, some proteins retain their normalexpression and distribution patterns and others are altered(32). This is similar to the findings in ADPKD.
In summary, we have demonstrated that both microcyst formationand HIV-1 infection of renal tubular epithelial cells occurin multiple nephron segments. The distribution of microcystformation and HIV-1 infection are similar, which is consistentwith a causal role for HIV-1 infection of tubular epithelialcells in microcyst formation. Loss of HIV-1 expression in epithelialcells lining microcysts may cause proliferation to cease, arrestingtubular dilation at the microcyst stage. Future studies definingthe viral genes responsible for epithelial proliferation andthe host responses that limit HIV-1 gene expression will helpclarify the molecular mechanisms for microcyst formation.
Acknowledgments
This work was supported by a fellowship grant from the NationalKidney Foundation of New York/New Jersey and by NIH Grant T32AI07623.
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Received for publication December 6, 2000.
Accepted for publication July 26, 2001.
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Abstract
Introduction
