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AIDS:
doi: 10.1097/QAD.0b013e32835f1ea1
Basic Science: Concise Communication

Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy

Gu, Leyia,b,*; Dai, Yana,c,*; Xu, Jina; Mallipattu, Sandeepa; Kaufman, Lewisa; Klotman, Paul E.d; He, John C.a,e; Chuang, Peter Y.a

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Author Information

aDivision of Nephrology, Mount Sinai School of Medicine, New York, New York, USA

bRenal Division and Molecular Cell Laboratory for Kidney Disease, Renji Hospital, Shanghai Jiaotong University School of Medicine

cDivision of Nephrology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

dBaylor College of Medicine, Houston, Texas

eRenal Section, James J Peter Veterans Affairs Medical Center, Bronx, New York, USA.

*Leyi Gu and Yan Dai contributed equally to the writing of this article.

Correspondence to Peter Y. Chuang, Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1243, New York, NY 10029, USA. Tel: +1 212 659 1752; fax: +1 212 831 0114; e-mail: peter.chuang@mssm.edu

Received 23 August, 2012

Revised 21 December, 2012

Accepted 17 January, 2013

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Abstract

Objective: HIV-1 gene expression in kidney epithelial cells is thought to be responsible for the pathogenesis of HIV-1-associated nephropathy (HIVAN). Signal transducer and activator of transcription (STAT) 3 signaling is activated in podocytes of patients with HIVAN and drives the dedifferentiation and proliferation of podocytes in culture. We confirm here that deletion of podocyte STAT3 is sufficient to mitigate the glomerular as well as tubulointerstitial findings of HIVAN.

Methods: To demonstrate the functional role of podocyte STAT3 in the pathogenesis of HIVAN we compared the development of HIVAN in Tg26 HIV-transgenic mice with and without deletion of STAT3 in the podocyte.

Results: Tg26 mice with podocyte-specific STAT3 deletion developed significantly less weight loss, albuminuria, and renal function impairment compared to Tg26 mice without STAT3 deletion. Tg26 mice with podocyte STAT3 deletion also had significantly less glomerular collapse, sclerosis, epithelial cell hyperplasia, podocyte dedifferentiation, and proinflammatory STAT3 target gene expression; and tubulointerstitial changes of HIVAN, including tubular atrophy, degeneration, apoptosis, and lymphocyte infiltration, were also significantly reduced compared to Tg26 mice without STAT3 deletion.

Conclusion: Development of glomerular as well as tubulointerstitial injuries in the Tg26 HIVAN model is dependent on podocyte STAT3 expression. Inhibition of STAT3 could be a potential adjunctive therapy for the treatment of HIVAN.

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Introduction

HIV-1-associated nephropathy (HIVAN) is a leading cause of end stage renal disease among HIV-1 seropositive patients with advanced HIV disease. Renal parenchymal features of HIVAN include focal segmental glomerulosclerosis, podocyte dedifferentiation and proliferation, tubular cell apoptosis, and tubular microcystic dilation [1]. With widespread use of combination antiretroviral therapy (cART), the impact of HIVAN has been dramatically reduced [2,3]. In spite of cART, however, some HIV-1 seropositive patients still progress to end stage renal failure. Furthermore, HIVAN remains a major health issue in Africa [4].

HIV-1 expression in the kidney epithelial cells is thought to be responsible for HIVAN pathogenesis [5]. When nonstructural components of the HIV-1 genome [6] or the gene encoding for the HIV-1 accessory protein nef [7] were overexpressed in podocytes of transgenic mice, podocytes dedifferentiated and acquired a proliferative phenotype. nef activates signal transducer and activator of transcription (STAT) 3 signaling and drives dedifferentiation and proliferation of cultured podocyte [8]. Consistent with this, STAT3 signaling is activated in podocytes of patients with HIVAN and the Tg26 murine model of HIVAN [8]. We demonstrated previously that Tg26 mice with global reduction of STAT3 activity were protected from the development of HIVAN, which suggests that STAT3 is required for podocyte proliferation [9]. However, since STAT3 expression is ubiquitous and reduction of STAT3 activity in our previous murine model was not cell specific, we could not distinguish the relative importance of STAT3 in different cell types (i.e. kidney vs. infiltrating inflammatory cells) for HIVAN pathogenesis. Here, we specifically examined the role of podocyte STAT3 on the development of HIVAN.

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Materials and methods

Animals

The classic HIV-transgenic mouse model, Tg26, is on the FVB/N background [10]. We generated mice with podocyte-specific deletion of Stat3 on the FVB/N background by backcrossing mice with a floxed Stat3 allele (STAT3f) [11] to FVB/N mice for six generations, which was then crossed to a line of FVB/N mice with podocyte-specific expression of Cre recombinase [12]. Subsequent F1 × F1 breeding of mice heterozygous for the STATf allele and positive for the Cre transgene (Cre+; STAT3f/+) yielded progeny with podocyte-specific deletion of STAT3 (Cre+; STAT3f/f) and control littermates without STAT3 deletion (Cre+; STAT3+/+).

Tg26 mice were bred with Cre+; STAT3f/f mice to generate Tg; Cre+; STAT3+/f mice. Male Tg; Cre+; STAT3+/f mice were crossed to female Cre+; STAT3+/f mice to generate the four groups of mice used in the experiments. Eight male mice per group were included. Four mice were killed at 4 and 7 weeks of age. Body weight, urine, and serum were obtained at the termination of the study. Studies were performed in accordance with the guidelines of and approved by the Institutional Animal Care and Use Committee at the Mount Sinai School of Medicine.

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Antibodies

A rabbit antibody against total STAT3 was purchased from Cell Signaling Technology (Danvers, Massachusetts, USA); a rabbit antibody against Wilm's Tumor 1 (WT-1) and a monoclonal antibody against nephrin were from Novus Biologicals (Littleton, Colorado, USA); a mouse antibody against actin was from Sigma Aldrich (St. Louis, Missouri, USA); a FITC-conjugated antibody against mouse CD3e antigen was from BD Pharmingen (San Jose, California, USA); a PE-conjugated antibody against mouse F4/80 antigen was from eBioscience (San Diego, California, USA); and a rabbit antibody against synaptopodin was a gift from Dr Peter Mundel (Massachusetts General Hospital, Boston, Massachusetts, USA).

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Primary podocyte culture

Glomeruli were extracted by perfusion of magnetic particles [13]. Extracted glomeruli were cultured on collagen-coated plates for 5 days in RPMI-1640 medium supplemented with 10% fetal bovin serum and 1% penicillin/streptomycin at 37°C. Five days later, cells were detached with 0.12% trypsin-EDTA solution, filtered through a 30 μmol/l filter and collected for western blotting.

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Western blot analysis

Western blotting was performed using 40–100 μg of denatured protein lysates per lane depending on the protein of interest as described previously [14].

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Histopathology, immunohistochemistry, and TUNEL staining of kidney tissue

Kidney samples were fixed in 10% formalin, embedded in paraffin, and sectioned to 4 μm thickness. Periodic Acid Schiff's stained sections were used for assessment of histologic changes. An examiner masked to the experimental condition quantified the extent of renal disorder using histologic criteria that had been described [9].

Kidney tissues embedded in OCT compound. Frozen sections were used for immunofluorescence staining of WT-1, STAT3, CD3, and F4/80. Results of immunofluorescence staining were imaged at 200× or 400× using a Zeiss Axioplan 2 IE microscope as previously described [15]. The percentage area of renal tissue covered by staining was quantified using ImageJ.

DeadEnd Colometric TUNEL System from Promega (Madison, Wisconsin, USA) was used to detect apoptotic cells. Formalin-fixed, paraffin-embedded kidney tissue were processed using manufacturer's protocol. Sections were incubated with the DAB chromogen for 9 min. For each mouse, more than 3 mm2 of renal tissue were assessed. Four mice per group were examined. Results are presented as number of TUNEL positive cells per mm2 of renal tissue.

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Quantification of serum urea nitrogen and urine albumin and creatinine

Serum urea nitrogen (SUN) and urine creatinine were quantified using commercial kits from BioAssay Systems (Hayward, California, USA). Urine albumin was determined using a commercial assay from Bethyl Laboratory Inc. (Houston, Texas, USA). Urine albumin excretion was expressed as the ratio of urine albumin to creatinine (UAC).

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Coomasie blue staining of urinary proteins

Five microlitres of urine were denatured with Laemmli sample buffer and then resolved on an 8% sodium dodecyl sulfate polyacrylamide gel by electrophoresis. Proteins on the gel were detected by Coomassie blue staining.

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Quantitative real time polymerase chain reaction

One microgram of total RNA extracted from glomerular extracts were reverse transcribed to complementary DNA, which was used in quantitative RT-PCR [14] with the following primer pairs: GCC ATC AAC GAC CCC TTC AT and ATG ATG ACC CGT TTG GCT CC for Gapdh, CAA AGC CAG AGT CCT TCA GAG and GCC ACT CCT TCT GTG ACT CC for interleukin 6 (Il6), CAC AGT TGC CGG CTG GAG CAT and GTA GCA GCA GGT GAG TGG GGC for chemokine C-C motif ligand 2 (Ccl2), CCC TCA CAC TCA GAT CAT CTT CT and GCT ACG ACG TGG GCT ACA G for tumor necrosis factor α (Tnfα), TTC TGG GGA GAG GGT GAG TT and GCC ATC CGA CTG CAT CTA TT for chemokine C-X-C motif ligand 2 (Cxcl2), GCC ATC TGG GCC AAA GAT ACC and GTC TTC GCA TGA ATA GGC CAA T for epidermal growth factor receptor (Egfr), CCG TGC AGT CGT CCG CTT CCG and GGG TCC GCG GTG CTC CAC CAT for intercellular adhesion molecule 1 (Icam1), and GGT CCC TCG CCC AGG TCC TT and GCG TGC TTC GGG GGT CAC TC for suppressor of cytokine signaling 3 (Socs3). Gene expression was normalized to Gapdh and fold change in expression relative to the Cre+; STAT3+/+ group (biological control) was calculated using the 2-ΔΔCt method. Three technical replicates per gene and four biological replicates (mice) per group were used.

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Statistical analysis

Data are expressed as mean ± SEM. For comparison of means between three or more groups, two-way ANOVA with Bonferroni posttest was applied. For comparisons of means between two groups, two-tailed, unpaired t-tests were performed. Prism 5 (Graphpad, La Jolla, California, USA) was used for statistical analyses.

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Results

Mice with podocyte-specific STAT3 deletion

Podocyte-specific deletion of STAT3 was confirmed by coimmunolabeling of STAT3 and a podocyte-specific marker, WT-1. Colabeling of STAT3 and WT-1 in the Cre+; STAT3f/f kidney was markedly less than the Cre+; STAT3+/+ kidney (Fig. 1a). Knockdown of podocyte STAT3 expression was also confirmed by western blotting for STAT3 in isolated primary podocytes (Fig. 1b).

Fig. 1
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Tg26 mice with podocyte STAT3 deletion developed less renal dysfunction
Fig. 1
Fig. 1
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To examine whether podocyte STAT3 deletion is sufficient to prevent the development of HIVAN in Tg26 mice, we compared the body weight, UAC, and SUN levels of Tg26 and non-Tg26 mice, with and without STAT3 deletion. Tg; Cre+; STAT3+/+ mice weighed significantly less than Cre+; STAT3+/+ mice at both 4 and 7 weeks of age (Fig. 1c, left panel, 15.8 ± 1.4 g vs. 19.9 ± 0.97 g and 21.9 ± 1.6 vs. 25.8 ± 0.51 g, n = 4 per group, P< 0.05). Body weight of Tg; Cre+; STAT3f/f mice were not significantly different from Cre+; STAT3+/+, Cre+; STAT3f/f, or Tg; Cre+; STAT3+/+ mice at 4 weeks of age, but were significantly higher than Tg; Cre+; STAT3+/+ mice at 7 weeks of age (25.6 ± 0.21 vs. 21.9 ± 1.6 g, n = 4 per group, P< 0.05).

Urinary albumin excretion, which is a marker of glomerular injury, was quantified by UAC. UAC of Tg; Cre+; STAT3+/+ mice was significantly higher than that of Cre+; STAT3+/+ mice at 4 and 7 weeks of age (Fig. 1c, middle panel, 2.81 ± 0.37 vs. 0.02 ± 0.01 mg/mg and 3.66 ± 0.61 vs. 0.03 ± 0.02 mg/mg, n = 4 per group, P< 0.001). UAC of Tg; Cre+; STAT3f/f mice was significantly lower than that of Tg; Cre+; STAT3+/+ mice at both 4 and 7 weeks of age (0.113 ± 0.05 vs. 2.81 ± 0.37 mg/mg and 0.87 ± 0.84 vs. 3.66 ± 0.61 mg/mg, n = 4 per group, P< 0.001), but was not significantly different from Cre+; STAT3+/+ and Cre+; STAT3f/f mice. Coomasie blue staining of urinary proteins revealed that proteins in the urine were predominately albumin (Fig. 1d). Freely filtered proteins (<20 kD) were observed in all urine samples, but consistently higher in 7-week-old mice for all groups. Urinary albumin for one of the two 7-week-old Tg; Cre+; STAT3f/f mice was more than the other 7-week-old Tg; Cre+; STAT3f/f mice and was also more than both of the 7-week-old Tg; Cre+; STAT3+/+ mice (Fig. 1d). This urine sample was collected from one of the four 7-week-old Tg; Cre+; STAT3f/f mice that had more severe pathologic features of HIVAN (Table 1).

Table 1
Table 1
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The level of SUN, which is inversely related to renal function, at 7 weeks of age was significantly higher in Tg; Cre+; STAT3+/+ mice compared with Tg; Cre+; STAT3f/f (Fig. 1c, right panel, 60.0 ± 17.8 vs. 31.1 ± 1.7 mg/dl, #P< 0.05, n = 4 per group), Cre+; STAT3+/+ mice (60.0 ± 17.8 vs. 26.9 ± 3.4 mg/dl, %P< 0.01, n = 4 per group), and Cre+; STATf/f mice (60.0 ± 17.8 vs. 28.2 ± 3.4 mg/dl, %P< 0.01, n = 4 per group). No significant difference in serum urea nitrogen was observed between the four groups at 4 weeks of age.

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Renal histology of Tg26 mice with and without STAT3 deletion

Kidney sections of 4 and 7-week-old mice were scored for glomerular and tubulointerstitial (T-I) features. Glomerular and T-I features of HIVAN were more severe in 7 vs. 4-week-old Tg; Cre+; STAT3+/+ mice (Table 1, representative pictures in Fig. 1e). Tg; Cre+; STAT3f/f mice had less glomeruli with collapse/sclerosis and a lower degree of glomerular epithelial hyperplasia compared with 4-week-old Tg; Cre+; STAT3+/+ mice. In fact, glomerular and T-I features were absent in all 4-week-old Tg; Cre+; STAT3f/f mice. In two of the 7-week-old Tg; Cre+; STAT3f/f mice, no glomerular or T-I HIVAN findings were observed. Although some glomerular and T-I pathologic features were observed in the other two 7-week-old Tg; Cre+; STAT3f/f mice, they were markedly less than 7-week-old Tg; Cre+; STAT3+/+ mice.

In HIVAN, apoptosis is observed in tubular cells, but not glomerular cells [16]. To determine where podocyte STAT3 deletion had any impact on tubular cell apoptosis in HIVAN kidneys, we performed TUNEL labeling (Fig. 1f). TUNEL staining was not observed in glomerular cells and in kidneys of non-Tg26 mice. The number of TUNEL positive cells per mm2 of renal tissue was significantly higher in 7-week-old Tg; Cre+; STAT3+/+ mice compared with Tg; Cre+; STAT3f/f mice (2.9 ± 0.4 vs. 0.75 ± 0.1 TUNEL positive cells per mm2 renal tissue, n = 4 per group, P = 0.0023, Fig. 1g).

To determine the effect of podocyte STAT3 deletion on mononuclear cell infiltration in HIVAN kidneys, we performed CD3 and F4/80 immunostaining for lymphocytes and macrophages, respectively. The percentage area of renal tissue with CD3 staining was significantly less in 7-week-old Tg; Cre+; STAT3+/+ mice compared with Tg; Cre+; STAT3f/f mice (0.55 ± 0.10 vs. 0.04 ± 0.02% area, n = 4 per group, P = 0.0021, Fig. 1g and h). F4/80 staining was not significantly different between 7-week-old Tg; Cre+; STAT3+/+ and Tg; Cre+; STAT3f/f mice (0.180 ± 0.10 vs. 0.16 ± 0.93% area, n = 4 per group, P > 0.05).

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Expression of podocyte differentiation markers and STAT3 target genes

Synaptopodin, a marker of podocyte differentiation, was markedly reduced in 7-week-old Tg; Cre+; STAT3+/+ kidney compared with other groups (Fig. 1i). Expression of other podocyte differentiation markers (i.e. nephrin and WT-1) were also reduced in the Tg; Cre+; STAT3+/+ kidneys, but preserved in Tg; Cre+; STAT3f/f kidneys, when compared to non-Tg26 kidneys (Fig. 1j).

The glomerular expressions of STAT3 target genes involved in inflammatory response – Il6, Ccl2, and Tnfα – were significantly higher in Tg; Cre+; STAT3+/+ mice compared to all other groups (Fig. 1k). Socs3 expression was significantly lower in Tg; Cre+; STAT3f/f compared with Tg; Cre+; STAT3+/+ mice. The glomerular expressions of other STAT3 target genes – Cxcl2, Egfr, and Icam1 – were not significantly different between the groups.

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Discussion

As STAT3 deletion was restricted to the podocytes of Tg; Cre+; STAT3f/f mice, we had anticipated those mice to develop less severe glomerular injury, but we had not expected them to be protected from tubular injury. Tg; Cre+; STAT3f/f mice developed less glomerular collapse, sclerosis, epithelial cell hyperplasia, and podocyte dedifferentiation; and they also had less tubular atrophy, degeneration, apoptosis, and lymphocyte infiltration compared to Tg; Cre+; STAT3+/+ mice. As the only difference between these two groups of mice is STAT3 expression in the podocytes, we concluded that manifestation of tubular disorder in Tg26 mice is dependent on the expression of podocyte STAT3.

Our findings are in line with the idea that glomerular injury precedes and likely predisposes to subsequent inflammation and apoptosis of tubular epithelial cells, which have been previously observed in HIVAN [16–19]. Consistent with our findings, transgenic mice with podocyte-specific expression of nonstructural HIV genes developed glomerular and podocyte abnormalities prior to the onset of tubular changes [6]. Although HIV-induced dysregulation of cytokinesis and apoptosis [19] as well as the expression of ubiquitin-like protein FAT10 [18] and proinflammatory mediators [17] have been reported in tubular epithelial cells, in light of our results, those mechanisms are more likely to be ancillary factors rather than direct initiators of tubular injury in HIVAN.

Cre-mediated deletion of STAT3 driven by the 2.5 kb human podocin promoter in the podocyte was incomplete based on our immunostaining and western blot results. This podocin-Cre line is widely used and incomplete Cre-mediated recombination in the podocytes has been reported [20,21]. Despite incomplete STAT3 silencing, Tg; Cre+; STAT3f/f mice were still protected from HIVAN, which suggests that podocyte STAT3 is an important driver in the pathogenesis of HIVAN. However, as STAT3 deletion was incomplete and Tg; Cre+; STAT3f/f mice were partially protected from HIVAN, it is not possible to determine whether the lack of complete protection was due to either incomplete STAT3 deletion or additional STAT3-independent pathogenic mechanisms. We suspect the answer is probably the latter as we and others have identified several other molecular mediators that also contribute to the pathogenesis of HIVAN (i.e. HIPK2 [15], MAPK1, 2 [8], TGF-β [22,23], sidekick-1 [24], VEGF [25]). However, the relationship of STAT3 with other pathogenic factors remains to be elucidated.

cART is the standard of care for treatment of HIVAN and the diagnosis of HIVAN is an indication for initiation of cART [26,27]. However, some patients with HIVAN still progress despite being on cART. Our study suggests that reduction of STAT3 activation could be a potential adjunctive therapeutic strategy for those patients. Direct STAT3 inhibitors [28] and kinase inhibitors of Janus kinases (JAK) [29,30], which are upstream nonreceptor tyrosine kinases that activate STAT3 signaling, have been studied in nonrenal diseases and could be used to inhibit STAT3 activity. As the JAK-STAT pathway is also a critical signaling pathway in diabetic nephropathy [31], we believe that our study could have a broader implication for other forms of kidney diseases that involve activation of JAK/STAT signaling. Future studies are needed to establish whether podocyte STAT3 plays a role in the development of diabetic nephropathy.

We conclude that podocyte STAT3 is required for the full manifestation of the HIVAN phenotype. These results further clarified the pathogenesis of HIVAN and could have an impact on the selection of therapeutic agents for the treatment of HIVAN and non-HIVAN kidney diseases.

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Acknowledgements

J.C.H. is supported by NIH 1R01DK078897 and 1R01DK088541–01A1 and a Veterans Affairs Merit Review Award 1I01BX000345; P.Y.C. is supported by NIH 5K08DK082760.

L.G., Y.D., and J.X. performed the experiments. L.G. and P.Y.C. analyzed the data. J.H. and P.Y.C. designed the experiments and authored the manuscript. S.M., L.K., and P.E.K. contributed to study design and discussion.

Source of Support: NIH R01DK078897, K08DK082760, R01DK088541–01A1, RC4DK090860, P01DK056492 and Veterans Affairs Merit Review Award 1I01BX000345.

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Conflicts of interest

The authors have no competing financial interests.

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Keywords:

dedifferentiation; glomerular disease; HIV-1-associated nephropathy; kidney; podocyte; STAT3

© 2013 Lippincott Williams & Wilkins, Inc.

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