KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Heon Yung Gee, Fujian Zhang, Shazia Ashraf, Stefan Kohl, Carolin E. Sadowski, Virginia Vega-Warner, Weibin Zhou, Svjetlana Lovric, Humphrey Fang, Margaret Nettleton, Jun Yi Zhu, Julia Hoefele, Lutz T. Weber, Ludmila Podracka, Andrej Boor, Henry Fehrenbach, Jeffrey W. Innis, Joseph Washburn, Shawn Levy, Richard P. Lifton & 3 others Edgar A. Otto, Zhe Han, Friedhelm Hildebrandt

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Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTPbound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.

Original languageEnglish
Pages (from-to)2375-2384
Number of pages10
JournalJournal of Clinical Investigation
Volume125
Issue number6
DOIs
Publication statusPublished - 2015 Jun 1

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Podocytes
Nephrotic Syndrome
Drosophila
GTP Phosphohydrolases
Steroids
Ankyrin Repeat
Exome
Kidney
Mutation
Zebrafish
RNA Interference
Diaphragm
Proteinuria
Genes
Phenotype

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Gee, H. Y., Zhang, F., Ashraf, S., Kohl, S., Sadowski, C. E., Vega-Warner, V., ... Hildebrandt, F. (2015). KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. Journal of Clinical Investigation, 125(6), 2375-2384. https://doi.org/10.1172/JCI79504
Gee, Heon Yung ; Zhang, Fujian ; Ashraf, Shazia ; Kohl, Stefan ; Sadowski, Carolin E. ; Vega-Warner, Virginia ; Zhou, Weibin ; Lovric, Svjetlana ; Fang, Humphrey ; Nettleton, Margaret ; Zhu, Jun Yi ; Hoefele, Julia ; Weber, Lutz T. ; Podracka, Ludmila ; Boor, Andrej ; Fehrenbach, Henry ; Innis, Jeffrey W. ; Washburn, Joseph ; Levy, Shawn ; Lifton, Richard P. ; Otto, Edgar A. ; Han, Zhe ; Hildebrandt, Friedhelm. / KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 6. pp. 2375-2384.
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Gee, HY, Zhang, F, Ashraf, S, Kohl, S, Sadowski, CE, Vega-Warner, V, Zhou, W, Lovric, S, Fang, H, Nettleton, M, Zhu, JY, Hoefele, J, Weber, LT, Podracka, L, Boor, A, Fehrenbach, H, Innis, JW, Washburn, J, Levy, S, Lifton, RP, Otto, EA, Han, Z & Hildebrandt, F 2015, 'KANK deficiency leads to podocyte dysfunction and nephrotic syndrome', Journal of Clinical Investigation, vol. 125, no. 6, pp. 2375-2384. https://doi.org/10.1172/JCI79504

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. / Gee, Heon Yung; Zhang, Fujian; Ashraf, Shazia; Kohl, Stefan; Sadowski, Carolin E.; Vega-Warner, Virginia; Zhou, Weibin; Lovric, Svjetlana; Fang, Humphrey; Nettleton, Margaret; Zhu, Jun Yi; Hoefele, Julia; Weber, Lutz T.; Podracka, Ludmila; Boor, Andrej; Fehrenbach, Henry; Innis, Jeffrey W.; Washburn, Joseph; Levy, Shawn; Lifton, Richard P.; Otto, Edgar A.; Han, Zhe; Hildebrandt, Friedhelm.

In: Journal of Clinical Investigation, Vol. 125, No. 6, 01.06.2015, p. 2375-2384.

Research output: Contribution to journalArticle

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AU - Zhou, Weibin

AU - Lovric, Svjetlana

AU - Fang, Humphrey

AU - Nettleton, Margaret

AU - Zhu, Jun Yi

AU - Hoefele, Julia

AU - Weber, Lutz T.

AU - Podracka, Ludmila

AU - Boor, Andrej

AU - Fehrenbach, Henry

AU - Innis, Jeffrey W.

AU - Washburn, Joseph

AU - Levy, Shawn

AU - Lifton, Richard P.

AU - Otto, Edgar A.

AU - Han, Zhe

AU - Hildebrandt, Friedhelm

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N2 - Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTPbound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.

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Gee HY, Zhang F, Ashraf S, Kohl S, Sadowski CE, Vega-Warner V et al. KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. Journal of Clinical Investigation. 2015 Jun 1;125(6):2375-2384. https://doi.org/10.1172/JCI79504