Disease modeling of ADAMTS9-related nephropathy using kidney organoids reveals its roles in tubular cells and podocytes

Seyoung Yu; Yo Jun Choi; John Hoon Rim; Hye-Youn Kim; Nasim Bekheirnia; Sarah Jane Swartz; Hongzheng Dai; Shen Linda Gu; Soyeon Lee; Ryuichi Nishinakamura; Friedhelm Hildebrandt; Mir Reza Bekheirnia; Heon Yung Gee

doi:10.3389/fmed.2023.1089159

Disease modeling of ADAMTS9-related nephropathy using kidney organoids reveals its roles in tubular cells and podocytes

Front Med (Lausanne). 2023 Mar 23:10:1089159. doi: 10.3389/fmed.2023.1089159. eCollection 2023.

Authors

Affiliations

¹ Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
² Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Department of Pediatrics, Division of Pediatric Nephrology, Baylor College of Medicine, Houston, TX, United States.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine/Baylor Genetics, Houston, TX, United States.
⁵ Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
⁶ Department of Medicine, Division of Nephrology, Boston Children's Hospital, Boston, MA, United States.
⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.

Abstract

Introduction: Mutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.

Methods: To investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids.

Results: ADAMTS9 knockout had no effect on nephron differentiation; however, it reduced the number of primary cilia, thereby recapitulating renal ciliopathy. Single-cell transcriptomics revealed that podocyte clusters express the highest levels of ADAMTS9, followed by the proximal tubules. Loss of ADAMTS9 increased the activity of multiple signaling pathways, including the Wnt/PCP signaling pathway, in podocyte clusters.

Conclusions: Mutations in ADMATS9 cause a glomerulotubular nephropathy in kidney and our study provides insights into the functional roles of ADMATS9 in glomeruli and tubules.

Keywords: ADAMTS9; Nephronophthisis-related ciliopathy; kidney organoid; podocytes; single-cell RNA sequencing.