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Nephrin Deficiency Activates NF-B and Promotes Glomerular Injury

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Nephrin Deficiency Activates NF-B and Promotes Glomerular Injury BASIC RESEARCH www.jasn.org Nephrin Deficiency Activates NF-␬B and Promotes Glomerular Injury Sagair Hussain,* Leile Romio,* Moin Saleem,† Peter Mathieson,† Manuel Serrano,‡ Jorge Moscat,§ Maria Diaz-Meco,§ Peter Scambler,* and Ania Koziell* *Molecular Medicine Unit, Institute of Child Health, London, and †Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, United Kingdom; ‡Spanish National Cancer Research Centre, Madrid, Spain; and §Department of Genome Science, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio ABSTRACT Increasing evidence implicates activation of NF-␬B in a variety of glomerular diseases, but the mechanisms involved are unknown. Here, upregulation of NF-␬B in the podocytes of transgenic mice resulted in glomer- ulosclerosis and proteinuria. Absence of the podocyte protein nephrin resulted in NF-␬B activation, suggest- ing that nephrin negatively regulates the NF-␬B pathway. Signal transduction assays supported a functional relationship between nephrin and NF-␬B and suggested the involvement of atypical protein kinase C (aPKC␨/␭/␫) as an intermediary. We propose that disruption of the slit diaphragm leads to activation of NF-␬B; subsequent upregulation of NF-␬B-driven genes results in glomerular damage mediated by NF-␬B-depen- dent pathways. In summary, nephrin may normally limit NF-␬B activity in the podocyte, suggesting a mechanism by which it might discourage the evolution of glomerular disease. J Am Soc Nephrol 20: 1733–1743, 2009. doi: 10.1681/ASN.2008111219 NF-␬B is a transcription factor activated by cell sur- of aPKC␨/␫ inhibitory proteins such as Par4 can also face receptor signaling to meet stress and inflam- abrogate NF-␬B activation.12,13 matory responses, regulating key cellular processes Glomerular disease manifests as urinary protein such as inflammation, innate and adaptive immu- leak resulting from malfunction of the glomerular nity, and cell growth and survival.1 Five mamma- filtration barrier. Podocytes separated by slit dia- lian NF-␬B proteins share a Rel homology domain phragms are crucial in maintaining barrier integ- with composition of the active dimer dictated by rity.14 Injury disrupts their actin cytoskeleton, caus- cell type and nature of inducing stimulus.2 Inactive ing foot process effacement; detachment from the NF-␬B is sequestered in the cytoplasm bound to glomerular basement membrane (GBM), with sig- I␬B3; phosphorylation of I␬B releases active NF-␬B, nificant molecular reorganization of the slit dia- which translocates to the nucleus to induce an ex- phragms; and urinary protein loss.15 tensive range of target genes.4 RelA dimers are the Nephrin, an Ig superfamily member, is a key slit dia- most abundant and potent gene transactivators phragm component and presumed adhesion molecule within the family.5 that contributes directly to a physical filtration barrier at Induction of NF-␬B signaling and specificity of transcriptional response are dependent on a com- Received November 30, 2008. Accepted March 17, 2009. plex interplay of pathways. Adaptor proteins p626 7 Published online ahead of print. Publication date available at and MyD88 and intracellular messengers such as www.jasn.org. atypical protein kinase C (aPKC␨/␫)8 connect ␬ ␨ ␫ Correspondence: Dr. Ania Koziell, Molecular Medicine Unit, In- NF- B with cell surface receptors. aPKC / acti- stitute of Child Health, 30 Guilford St, London, WC1N 1EH, UK. vates NF-␬B by either release from I␬B9 or direct Phone: 00-44-207-242-9789, ext. 0713, 00-44-783-481-4994; nuclear phosphorylation,10 whereas activation is se- Fax: 00-44-207-905-2609; E-mail: [email protected] verely impaired by aPKC␨ deficiency.11 Expression Copyright ᮊ 2009 by the American Society of Nephrology J Am Soc Nephrol 20: 1733–1743, 2009 ISSN : 1046-6673/2008-1733 1733 BASIC RESEARCH www.jasn.org the slit diaphragm.16,17 Nephrin muta- tions result in disruption of the actin cytoskeleton and severe glomerular disease. Downregulation of nephrin ex- pression unrelated to gene mutations also occurs in podocyte injury,18,19 and mutations that are within the cytosolic tail and do not affect protein expression cause equivalent glomerular dis- ease,20,21 supporting a role in cellular signaling. This is verified by evidence that nephrin serves as a signaling scaf- fold to recruit other podocyte pro- teins,22–25 is phosphorylated by Src- family kinases,26,27 and associates with adapters such as Nck to regulate the ac- tin cytoskeleton.28,29 To our knowledge, the mechanism of NF-␬B regulation in glomerular cells is unknown. Evidence for the involve- ment of NF-␬B activation in glomeru- lar and renal tubular cell injury is pro- vided by correlative studies of human Figure 1. Glomerular disease is present in Par4Ϫ/Ϫ mice. (A) A total of 4 ␮l of urine from kidney disease30,31 and experimental 3-mo-old WT (WT1 and WT2) and Par4Ϫ/Ϫ (KO1 through 6) mice was suspended in Laemmli disease models.31,32 Complement acti- buffer and subjected to SDS-PAGE. Coomassie staining detected proteinuria in Par4Ϫ/Ϫ mice but vates NF-␬B and NF-␬B–dependent not their WT counterparts. A band corresponding to albumin is shown (68 kD; black arrow). The gene transcription in podocytes in variability in proteinuria resolved with increasing age of mice. (B) Hematoxylin and eosin staining of Par4Ϫ/Ϫ and WT glomeruli at 2 wk (a and b), 3 mo (c and d), and 6 mo (e and f). At 2 wk, only vitro,33 and upregulation of IL-1, IL-4, mild mesangial hypercellularity and glomerular enlargement is present in Par4Ϫ/Ϫ glomeruli, with and TNF-␣is detected in injured podo- preservation of the tubulointerstitial compartment (a). At 3 mo, marked mesangial expansion, cytes, supporting a direct role for glomerulosclerosis, and widening of the subcapsular space is evident, with some capsular adhe- ␬ NF- B activation in human glomerular sions (c). Significant disease progression occurs by 6 mo, with widespread scarring and atrophy of disease.30,31 Whether nephrin modu- glomeruli, tubular atrophy, and pseudocysts containing proteinaceous material (arrow; E). In 25% lates NF-␬B has not been investigated, of mice, coexisting renal tubular cysts were lined by simple epithelium (*), which also progressed but regulation of NF-KB activation by in severity with age. Glomeruli and renal tubules were normal at all ages in WT controls (B, D, and other Ig superfamily molecules in- F). (C) Par4Ϫ/Ϫ glomeruli were also abnormal at the ultrastructural level (c through h). In 2-wk-old volved in cell adhesion, namely N-Cam mice (c and d), there is discontinuous podocyte foot process effacement and mild cell body and L1Ig6, is well described.33,34 swelling, but the GBM is normal. By 3 mo, there is marked effacement and swelling with hyaline We investigated a causal link be- deposits and vacuoles, glomerulosclerosis, mesangial expansion, and patchy blebbing of the GBM tween NF-␬B activation and renal (e and f). By 6 mo, podocyte swelling, sclerosis, and foot process fusion is extensive, with diffuse thickening, corrugation, and denudation of the GBM. The mesangial matrix is folded and col- glomerular damage by examining lapsed (g and h). By contrast, normal podocyte and glomerular architecture is seen in WT mice and whether genetic inactivation of an littermates (a and b). Podocyte foot processes are well demarcated, and the mesangium is normal ␬ upstream inhibitor of NF- B acti- with preservation of the urinary space and no tubular cysts. Magnifications: ϫ40 in B; ϫ300 in C vation could result in glomerular in- (a, c, e, and g); ϫ6000 in C (b, d, f, and h). jury independent of immune cell activation. Considering its ubiquitous role in maintaining glo- notype has been reported in conjunction with mouse models merular filtration, we then explored whether the receptor pro- resulting in NF-␬B deficiency, we examined the significance of tein nephrin participates in the regulation of this process. NF-␬B activation in the kidney in vivo, focusing on models with constitutive activation of NF-␬B resulting from removal of natural pathway inhibition. This conventional approach en- ␬ RESULTS ables study of NF- B overexpression while avoiding off-target effects.35 Activation of NF-␬B Results in Glomerulosclerosis and One such model involves genetic inactivation of the prostate Proteinuria In Vivo apoptosis response 4 gene (Par4), which specifically binds and We first tested the hypothesis that NF-␬B activation is a key inhibits aPKC␨/␭/␫ and is a critical negative regulator of the RelA/ response leading to glomerular damage. Because no renal phe- NF-␬B pathway.12,13 Disruption of Par4 through homologous re- 1734 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 1733–1743, 2009 www.jasn.org BASIC RESEARCH combination in outbred (CD1) wild-type (WT) mice resulted in de-repression of aPKC␨/␭/␫ and activation of NF-␬B.36 Al- though Par4 is ubiquitously expressed, no clear systemic phenotype was identified. We therefore examined Par4Ϫ/Ϫ mice for renal abnormalities. Par4Ϫ/Ϫ mice were studied at 2 wk, 3 mo, and 6 mo (n ϭ 40). Although mice ini- tially seemed normal, by 3 mo, the majority had developed significant proteinuria (Fig- ure 1A). Analysis of kidneys by light micros- copy at 2 wk showed mild mesangial expan- sion within glomeruli and ultrastructural evidence of foot process fusion indicative of a primary podocyte defect, supported by ev- idence of some podocyte loss on electron microscopy (Figures 1, Ba and C, c and d). At 3 mo, increasingly severe glomeruloscle- Figure 2. RelA and aPKC␨/␭/␫ are activated in Par4Ϫ/Ϫ podocytes. (A) Double- rosis was apparent with hyalinosis, tubular immunofluorescence staining of WT and Par4Ϫ/Ϫ glomeruli showing expression of atrophy, pseudocysts, and luminal deposi- RelA/NF-␬B (a and b) and acetylated tubulin (c and d) in murine podocytes (white tion of proteinaceous material (Figure 1Bc).
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