Yiqing Guo1, Jesse Pace1, Zhengzhe Li2, Avi Ma'ayan3, Zichen Wang3, Monica P Revelo4, Edward Chen3, Xiangchen Gu1, Ahmed Attalah1, Yaqi Yang1, Chelsea Estrada1, Vincent W Yang5, John C He2,3,6, Sandeep K Mallipattu7,8. 1. Divisions of Nephrology and. 2. Division of Nephrology, Department of Medicine and. 3. Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Department of Pathology, University of Utah, Salt Lake City, Utah. 5. Gastroenterology, Department of Medicine, Stony Brook University, Stony Brook, New York. 6. Renal Section, James J. Peters Veterans Affairs Medical Center, New York, New York; and. 7. Divisions of Nephrology and sandeep.mallipattu@stonybrookmedicine.edu. 8. Renal Section, Northport Veterans Affairs Medical Center, Northport, New York.
Abstract
BACKGROUND: Podocyte injury is the hallmark of proteinuric kidney diseases, such as FSGS and minimal change disease, and destabilization of the podocyte's actin cytoskeleton contributes to podocyte dysfunction in many of these conditions. Although agents, such as glucocorticoids and cyclosporin, stabilize the actin cytoskeleton, systemic toxicity hinders chronic use. We previously showed that loss of the kidney-enriched zinc finger transcription factor Krüppel-like factor 15 (KLF15) increases susceptibility to proteinuric kidney disease and attenuates the salutary effects of retinoic acid and glucocorticoids in the podocyte. METHODS: We induced podocyte-specific KLF15 in two proteinuric murine models, HIV-1 transgenic (Tg26) mice and adriamycin (ADR)-induced nephropathy, and used RNA sequencing of isolated glomeruli and subsequent enrichment analysis to investigate pathways mediated by podocyte-specific KLF15 in Tg26 mice. We also explored in cultured human podocytes the potential mediating role of Wilms Tumor 1 (WT1), a transcription factor critical for podocyte differentiation. RESULTS: In Tg26 mice, inducing podocyte-specific KLF15 attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation, while improving renal function and overall survival; it also attenuated podocyte injury in ADR-treated mice. Enrichment analysis of RNA sequencing from the Tg26 mouse model shows that KLF15 induction 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 WT1. CONCLUSIONS: Inducing podocyte-specific KLF15 attenuates kidney injury by directly and indirectly upregulating genes critical for podocyte differentiation, suggesting that KLF15 induction might be a potential strategy for treating proteinuric kidney disease.
BACKGROUND: Podocyte injury is the hallmark of proteinuric kidney diseases, such as FSGS and minimal change disease, and destabilization of the podocyte's actin cytoskeleton contributes to podocyte dysfunction in many of these conditions. Although agents, such as glucocorticoids and cyclosporin, stabilize the actin cytoskeleton, systemic toxicity hinders chronic use. We previously showed that loss of the kidney-enriched zinc finger transcription factor Krüppel-like factor 15 (KLF15) increases susceptibility to proteinuric kidney disease and attenuates the salutary effects of retinoic acid and glucocorticoids in the podocyte. METHODS: We induced podocyte-specific KLF15 in two proteinuric murine models, HIV-1 transgenic (Tg26) mice and adriamycin (ADR)-induced nephropathy, and used RNA sequencing of isolated glomeruli and subsequent enrichment analysis to investigate pathways mediated by podocyte-specific KLF15 in Tg26 mice. We also explored in cultured human podocytes the potential mediating role of Wilms Tumor 1 (WT1), a transcription factor critical for podocyte differentiation. RESULTS: In Tg26 mice, inducing podocyte-specific KLF15 attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation, while improving renal function and overall survival; it also attenuated podocyte injury in ADR-treated mice. Enrichment analysis of RNA sequencing from the Tg26 mouse model shows that KLF15 induction 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 WT1. CONCLUSIONS: Inducing podocyte-specific KLF15 attenuates kidney injury by directly and indirectly upregulating genes critical for podocyte differentiation, suggesting that KLF15 induction might be a potential strategy for treating proteinuric kidney disease.
Authors: Martin Kann; Sandrine Ettou; Youngsook L Jung; Maximilian O Lenz; Mary E Taglienti; Peter J Park; Bernhard Schermer; Thomas Benzing; Jordan A Kreidberg Journal: J Am Soc Nephrol Date: 2015-01-30 Impact factor: 10.121
Authors: Sandeep K Mallipattu; Emily J Gallagher; Derek LeRoith; Ruijie Liu; Anita Mehrotra; Sylvia J Horne; Peter Y Chuang; Vincent W Yang; John C He Journal: Am J Physiol Renal Physiol Date: 2014-03-05
Authors: Carl F Schaefer; Kira Anthony; Shiva Krupa; Jeffrey Buchoff; Matthew Day; Timo Hannay; Kenneth H Buetow Journal: Nucleic Acids Res Date: 2008-10-02 Impact factor: 16.971
Authors: Sian E Piret; Ahmed A Attallah; Xiangchen Gu; Yiqing Guo; Nehaben A Gujarati; Justina Henein; Amy Zollman; Takashi Hato; Avi Ma'ayan; Monica P Revelo; Kathleen G Dickman; Chung-Hsin Chen; Chia-Tung Shun; Thomas A Rosenquist; John C He; Sandeep K Mallipattu Journal: Kidney Int Date: 2021-10-09 Impact factor: 10.612
Authors: Jesse A Pace; Robert Bronstein; Yiqing Guo; Yaqi Yang; Chelsea C Estrada; Nehaben Gujarati; David J Salant; John Haley; Agnieszka B Bialkowska; Vincent W Yang; John C He; Sandeep K Mallipattu Journal: Sci Adv Date: 2021-09-03 Impact factor: 14.136