Podocyte-specific induction of Krüppel-like factor 15 restores differentiation markers and attenuates kidney injury in proteinuric kidney disease
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PROVIDER: PRJNA483939 | ENA |
REPOSITORIES: ENA
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Project description:Podocyte injury is the hallmark of proteinuric kidney diseases, such as Focal Segmental Glomerulosclerosis and Minimal Change Disease. Therapeutic strategies in the management of proteinuric diseases are limited. Although agents such as glucocorticoids, cyclosporine, and rituximab have direct effects on the podocyte by stabilizing its actin cytoskeleton, these drugs are riddled with systemic toxicity and off-target effects that hinder their chronic use. We previously demonstrated that the loss of the kidney-enriched zinc finger transcription factor, Krüppel-like factor 15 (KLF15), increases susceptibility to proteinuric kidney disease as well as attenuates the salutary effects of retinoic acid and glucocorticoids in the podocyte. Here, we show that podocyte-specific induction of KLF15, using the tetracycline-inducible system, attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis and inflammation, while improving renal function and overall survival in HIV-1 transgenic mice. Enrichment analysis of mRNA sequencing of isolated glomerular extracts from this model shows that podocyte-specific induction of KLF15 activates pathways involved in stabilization of actin cytoskeleton, focal adhesion, and podocyte differentiation. Transcription factor enrichment analysis, with further experimental validation, suggests that KLF15 activity is in part mediated by Wilms Tumor 1 (WT1), a transcription factor known to be critical for podocyte differentiation. Further, we confirmed the benefits of podocyte-specific induction of KLF15 in the adriamycin-induced proteinuric murine model. Collectively, these observations suggest that induction of KLF15 might be a potential therapeutic target in the treatment of proteinuric kidney disease.
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Project description:The progression of proteinuric kidney disease is associated with podocyte loss but the mechanisms remain unclear. Podocytes reenter the cell cycle to repair damaged ds DNA breaks. However, unsuccessful repair results in podocytes crossing the G1/S checkpoint and undergoes abortive cytokinesis. In this study, we identified Pfn1 as a major contributor in maintaining glomerular integrity and its loss in mice results in severe proteinuria, and kidney failure due to podocyte mitotic catastrophe, characterized by abundant multinucleated cells. Reentry of podocytes were identified by using FUCCI-2aR mice, accompanying the alteration of cell-cycle associated proteins, such as P21, P53, Cyclin B, and Cyclin D. Podocyte-specific translating ribosome affinity purification (TRAP) and RNAseq revealed a reduction of Ribosomal RNA-processing protein 8 (Rrp8) and re-expression of Rrp8 partially rescued the in-vitro phenotype. Clinical analysis of patients with proteinuric kidney disease demonstrated multinucleated podocytes and reduced podocyte profilin1 in kidney tissue. These results suggest that profilin is indispensible in regulating podocyte cell cycle and its disruption contributes to podocyte loss through mitotic catastrophe.
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Project description:To investigate the alterations in cell populations in the kidney after podocyte DNA DSBs, we performed single-cell RNA sequencing (scRNA-seq) on the renal cortex of 12-week-old podocyte-specific I-PpoI expressing mice that had not yet developed glomerulosclerosis or fibrosis.
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Project description:Evidence for reduced expression of cyclin-G associated kinase (GAK) in glomeruli of chronic kidney disease patients was observed in the Nephroseq human database and was found to be associated with the decline in kidney function. To examine the role of GAK, a protein that functions to uncoat clathrin during endocytosis, we generated podocyte-specific Gak knockout mice (Gak KO) which developed progressive proteinuria and kidney failure with global glomerulosclerosis. We isolated glomeruli from the mutant mice to perform messenger RNA profiling and unearthed evidence for dysregulated podocyte calpain protease activity as an important contributor to this process. Treatment with calpain inhibitor III specifically inhibited calpain-1/-2 activities, mitigated the degree of proteinuria and glomerulosclerosis, and led to a striking increase in survival in the Gak KO mice. Podocyte-specific deletion of Capns1, essential for calpain-1 and calpain-2 activities, also improved proteinuria and glomerulosclerosis in Gak KO mice. Increased podocyte calpain activity mediated proteolysis of IkB resulted in increased NF-kBp65 induced Gadd45b expression in the Gak KO mice. Our results suggest that loss of podocyte associated Gak induces glomerular injury secondary to calcium dysregulation and aberrant calpain activation, which when inhibited, can provide a protective role.
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Project description:Podocyte injury in diabetic kidney disease contributes to the development of albuminuria and subsequent renal decline. Clinically, gastric bypass surgery is associated with reductions in albuminuria, and rodent studies demonstrate coherent improvements in renal histology. We aimed to investigate the mechanisms underpinning remission of albuminuria following gastric bypass focussing on podocyte injury. Firstly, we tracked the evolution of albuminuria and cognate evidence of histological and ultrastructural damage to the glomerulus in male Zucker Diabetic Fatty rats. Secondly, we examined the impact of gastric bypass in these rats, focussing on podocyte injury. Thirdly, we conducted a global transcriptomic study profiling the shift in the renal transcriptome in the Zucker Diabetic Fatty rats rat and its relevance to human disease. Lastly, we explored whether gastric bypass could reverse the changes seen in the disease associated transcriptome. Albuminuria in the Zucker Diabetic Fatty rat developed by 12 weeks of age. This was accompanied by glomerulomegaly, podocyte stress and ultrastructural evidence of podocyte dedifferentiation. When animals underwent gastric bypass at 12 weeks of age, marked reductions in albuminuria in association with normalisation of glomerular tuft size, attenuation of podocyte stress and improvements in podocyte foot process morphology were observed within 2 months of surgery. A characteristic disease associated gene expression signature was observed in the kidneys of Zucker Diabetic Fatty rats, with a core set of alterations conserved in global analysis of the human DKD transcriptome. Many of the shared gene expression alterations were reversed by gastric bypass. Reductions in podocyte injury represent a key mechanism underpinning the remission of albuminuria following gastric bypass.
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Project description:Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement (ERT) or chaperone mediated stabilization, thereby alleviating lysosome dysfunction. However, the therapeutic effect in the regression of end-organ damage (ie. kidney damage) is limited. Ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not alter podocyte injury. A novel CRISPR-/CAS9-mediated -Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptomic-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury.
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Project description:Podocyte injury is involved in the onset and progression of various kidney diseases. We previously demonstrated that the transcription factor, old astrocyte specifically induced substance (OASIS) in myofibroblasts, contributes to kidney fibrosis, as a novel role of OASIS in the kidneys. Importantly, we found that OASIS is also expressed in podocytes; however, the pathophysiological significance of OASIS in podocytes remains unknown. Upon lipopolysaccharide (LPS) treatment, there is an increase in OASIS in murine podocytes. Enhanced serum creatinine levels and tubular injury, but not albuminuria and podocyte injury, are attenuated upon podocyte-restricted OASIS knockout in LPS-treated mice, as well as diabetic mice. The protective effects of podocyte-specific OASIS deficiency on tubular injury are mediated by protein kinase C iota (PRKCI/PKCι), which is negatively regulated by OASIS in podocytes. Furthermore, podocyte-restricted OASIS transgenic mice show tubular injury and tubulointerstitial fibrosis, with severe albuminuria and podocyte degeneration. Finally, there is an increase in OASIS-positive podocytes in the glomeruli of patients with minimal change nephrotic syndrome and diabetic nephropathy. Taken together, OASIS in podocytes contributes to podocyte and/or tubular injury, in part through decreased PRKCI. The induction of OASIS in podocytes is a critical event for the disturbance of kidney homeostasis.
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