Podocyte-specific KLF6 primes proximal tubule CaMK1D signaling to attenuate diabetic kidney disease

Nehaben A. Gujarati, Bismark O. Frimpong, Malaika Zaidi, Robert Bronstein, Monica P. Revelo, John D. Haley, Igor Kravets, Yiqing Guo and Sandeep K. Mallipattu ()
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Nehaben A. Gujarati: Stony Brook University
Bismark O. Frimpong: Stony Brook University
Malaika Zaidi: Stony Brook University
Robert Bronstein: Stony Brook University
Monica P. Revelo: University of Utah
John D. Haley: Stony Brook University
Igor Kravets: Stony Brook University
Yiqing Guo: Stony Brook University
Sandeep K. Mallipattu: Stony Brook University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Diabetic kidney disease (DKD) is the main cause of chronic kidney disease worldwide. While injury to the podocytes, visceral epithelial cells that comprise the glomerular filtration barrier, drives albuminuria, proximal tubule (PT) dysfunction is the critical mediator of DKD progression. Here, we report that the podocyte-specific induction of human KLF6, a zinc-finger binding transcription factor, attenuates podocyte loss, PT dysfunction, and eventual interstitial fibrosis in a male murine model of DKD. Utilizing combination of snRNA-seq, snATAC-seq, and tandem mass spectrometry, we demonstrate that podocyte-specific KLF6 triggers the release of secretory ApoJ to activate calcium/calmodulin dependent protein kinase 1D (CaMK1D) signaling in neighboring PT cells. CaMK1D is enriched in the first segment of the PT, proximal to the podocytes, and is critical to attenuating mitochondrial fission and restoring mitochondrial function under diabetic conditions. Targeting podocyte-PT signaling by enhancing ApoJ-CaMK1D might be a key therapeutic strategy in attenuating the progression of DKD.

Date: 2024
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DOI: 10.1038/s41467-024-52306-5

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