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Janus Kinase 2 Regulates Transcription Factor EB Expression and Autophagy Completion in Glomerular Podocytes

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Janus Kinase 2 Regulates Transcription Factor EB Expression and Autophagy Completion in Glomerular Podocytes BASIC RESEARCH www.jasn.org Janus Kinase 2 Regulates Transcription Factor EB Expression and Autophagy Completion in Glomerular Podocytes Tamadher A. Alghamdi,* Syamantak Majumder,* Karina Thieme,* Sri N. Batchu,* † Kathryn E. White, Youan Liu,* Angela S. Brijmohan,* Bridgit B. Bowskill,* ‡ Suzanne L. Advani,* Minna Woo, and Andrew Advani* *Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada; †Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne, United Kingdom; and ‡Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada ABSTRACT The nonreceptor kinase Janus kinase 2 (JAK2) has garnered attention as a promising therapeutic target for the treatment of CKD. However, being ubiquitously expressed in the adult, JAK2 is also likely to be necessary for normal organ function. Here, we investigated the phenotypic effects of JAK2 deficiency. Mice in which JAK2 had been deleted from podocytes exhibited an elevation in urine albumin excretion that was accompanied by increased podocyte autophagosome fractional volume and p62 aggregation, which are indicative of impaired autophagy completion. In cultured podocytes, knockdown of JAK2 sim- ilarly impaired autophagy and led to downregulation in the expression of lysosomal genes and decreased activity of the lysosomal enzyme, cathepsin D. Because transcription factor EB (TFEB) has recently emerged as a master regulator of autophagosome-lysosome function, controlling the expression of sev- eral of the genes downregulated by JAK2 knockdown, we questioned whether TFEB is regulated by JAK2. In immortalized mouse podocytes, JAK2 knockdown decreased TFEB promoter activity, expression, and nuclear localization. In silico analysis and chromatin immunoprecipitation assays revealed that the down- stream mediator of JAK2 signaling STAT1 binds to the TFEB promoter. Finally, overexpression of TFEB in JAK2-deficient podocytes reversed lysosomal dysfunction and restored albumin permselectivity. Collec- tively, these observations highlight the homeostatic actions of JAK2 in podocytes and the importance of TFEB to autophagosome-lysosome function in these cells. These results also raise the possibility that therapeutically modulating TFEB activity may improve podocyte health in glomerular disease. J Am Soc Nephrol 28: 2641–2653, 2017. doi: https://doi.org/10.1681/ASN.2016111208 Podocytes are in a unique situation. As terminally dif- organelles. They also depend on intrinsic survival sig- ferentiated epithelial cells with interdigitating feet that nals, among them signals that are mediated by the encompass the capillary walls within the glomerular nonreceptor kinase, Janus kinase 2 (JAK2).2 tuft, they are uniquely exposed to metabolic shifts and hemodynamic pressures that render them vulnerable to injury in glomerular disease. Where the potential Received November 14, 2016. Accepted March 20, 2017. for regeneration and replacement is limited, podocytes Published online ahead of print. Publication date available at depend heavily on their use of homeostatic pathways www.jasn.org. to mitigate the pressures that they face. For instance, Correspondence: Dr. Andrew Advani, St. Michael’sHospital, they possess a high basal rate of macroautophagy 6-151, 61 Queen Street East, Toronto, ON, Canada M5C 2T2. (henceforth referred to as autophagy),1 aself-degradative Email: [email protected] process that removes protein aggregates and damaged Copyright © 2017 by the American Society of Nephrology J Am Soc Nephrol 28: 2641–2653, 2017 ISSN : 1046-6673/2809-2641 2641 BASIC RESEARCH www.jasn.org The JAK/Signal Transduction and Activation of Transcrip- (Supplemental Figure 1). Second, to generate podocyte-specific fl fl tion (STAT) pathway is an intracellular signaling cascade that JAK2 knockout animals, we bred Podocin-cre+ mice with Jak2 / regulates cell growth, proliferation, and differentiation.3 Of the mice in which loxP sites had been placed around the promoter four JAK family members (JAK1, JAK2, JAK3, and tyrosine and first coding exon of Jak2.19 We studied two groups of mice: fl fl kinase 2), the JAK2 isoform has become a focus of accelerated Podocin-cre+Jak2+/+ mice and Podocin-cre+Jak2 / mice, hence- drug discovery attentions since 2005, when activating muta- forth referred to as JAK2Ctrl and JAK2podKO, respectively. Both tions of its encoding gene were first shown to underlie the groups of mice were born in the expected Mendelian frequency. development of certain myeloproliferative neoplasias.4 In kid- To determine the efficiency of JAK2 deletion, we isolated pri- ney disease, evidence of JAK/STAT pathway activation in hu- mary cultured podocytes from JAK2Ctrl and JAK2podKO mice. man diabetic nephropathy5,6 encouraged the repurposing of Primary cultured podocytes were recognizable by their arbor- the JAK1/2 inhibitor baricitinib, and this was recently shown ized morphology and the expression of the podocyte protein to reduce albuminuria and markers of renal inflammation in a nephrin on immunoblotting (Figure 1B). JAK2 deletion from phase 2 study.7 podocytes in JAK2podKO mice was confirmed by (1)immuno- Although current advances have shone the spotlight on JAK/ blotting (Figure 1C) and (2)immunofluorescence microscopy STAT signaling as a promising treatment target for kidney dis- (Figure 1D). ease,8 this is not itself a new concept. It has been a decade and a In adult mice (age 10 weeks old), the magnitude of urine half since JAK2-mediated signaling was first implicated in the albumin excretion in JAK2podKO mice was almost double that development of kidney inflammation and fibrosis, an inference of their littermate controls (Figure 1E, Supplemental Table 1). fl that came about with the publication of a collection of reports Albuminuria in Podocin-cre+Jak2 /+ heterozygous mice fell describing its actions in glomerular mesangial cells.9–11 Since midway between the levels seen in JAK2Ctrl and JAK2podKO then, podocyte preservation has gained increasing traction for mice (urine albumin excretion, 2264 mg/d; n=13). By 6 its importance in preventing both the initiation and propagation months of age, urine albumin excretion was increased three- of glomerular disease,12,13 and in contrast to the studies in rep- fold in JAK2podKO mice(Figure1E).Insubsequentexperi- licating mesangial cells, the few reports that have examined the ments, we focused our analyses on the structural changes actions of JAK2 in podocytes have cited the kinase as being a that occurred in mice at the earlier (10 weeks) time point, mediator of cell survival.2,14 which we speculated were more likely to be causatively impli- Cognizant of the growing interest in therapeutic applica- cated in the development of albuminuria. At this stage, glo- tions that alter JAK/STAT signaling in kidney disease and the merular morphology in JAK2podKO mice was unremarkable dearth of literature espousing the homeostatic actions of the when assessed by light microscopy (Supplemental Figure 2). pathway in podocytes, we set out to examine the phenotypic In contrast, when we examined the ultrastructure of podocytes effects of JAK2 absence. To our surprise, we found that JAK2 by transmission electron microscopy, we observed an approx- deficiency in mice led to an impairment in autophagy in po- imately 80% increase in autophagosome fractional volume in docytes, and in exploring the means by which this occurred, we JAK2podKO mice (Figure 1F). Similarly, in primary podocytes identified a hitherto unrecognized action of JAK2 in control- from JAK2podKO mice, there was an increase in abundance of LC3- ling the expression of the master regulator of autophagy15 and II, the autophagosome-associated phosphatidylethanolamine- lysosome function,16 transcription factor EB (TFEB). conjugated form of the protein microtubule-associated protein 1A/1B–light chain 3 (LC3)20 (Figure 1G). We considered that increased autophagosome fractional volume and LC3-II levels RESULTS could be due to either enhanced induction of autophagy or impaired completion of autophagy. To help us distinguish Knockout of JAK2 from Podocytes Impairs Autophagy between these two scenarios, we probed for the autophagy sub- Completion in Mice strate, p62 (also called sequestosome 1), that accumulates in Toexamine the normal actions of JAK2-dependent signaling in the cytosol when autophagy is impaired.21 In comparison with podocytes, we generated podocyte-specificJAK2knockout JAK2Ctrl mice and suggestive of impaired autophagy comple- mice. First, to confirm that Cre recombinase expression was tion, there was an increase in podocyte p62 in JAK2podKO mice limited to the glomerulus, we bred Podocin-cre+ mice17 with (Figure 1, H and I). This impairment in autophagy completion fl fl ROSA26 reporter mice (R26R / ).18 Histologic staining of kid- was accompanied by an increase in lysosome accumulation as 2 ney sections from Podocin-cre mice showed no expression of assessed by immunostaining and immunoblotting for the b-galactosidase, whereas b-galactosidase was strongly ex- lysosome marker lysosome-associated membrane protein 2 fl fl pressed in the kidneys of Podocin-cre+R26R / mice, where (LAMP2) (Figure 1, J and K). it was constrained to the glomeruli (Figure 1A). To examine whether the presence of the cre transgene affects podocyte JAK2 Knockdown Impairs Autophagy Completion in 2 permselectivity, we followed Podocin-cre and Podocin-cre+ Differentiated Immortalized Podocytes mice for 6 months, observing no difference
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