Abstract
Low nephron endowment constitutes a risk factor for hypertension and renal disease. Epigenetic regulation is crucial for nephron progenitor cell differentiation, affecting nephron number and renal function. The role of many epigenetic modulators, such as Lysine-specific histone demethylase 1a (LSD1 or KDM1A), remains unclear. We used Kdm1a-KO mice to demonstrate that Kdm1a depletion in nephron progenitor cells results in reduced kidney size in neonates and led to glomerulosclerosis, proteinuria, and renal cysts in adults. Notably, Kdm1a deletion in podocytes or tubular cells did not replicate these effects. CRISPR/Cas9-mediated KDM1A deletion in human kidney organoids caused cyst formation and altered gene expression, with snRNA-seq revealing downregulation of podocyte genes and upregulation of metabolic genes. The presence of noncoding RNAs indicated roles in cell proliferation. Our study reveals the critical role of Kdm1a function in nephron development and highlights its affect on transcriptional programming for long-term renal function and susceptibility to cyst formation.
Authors
Nicola Wanner, Julia Keller, Nastassia Liaukouskaya, Geoffroy Andrieux, Sandra D. Laufer, Manuel Rogg, Tillmann Bork, Wei Liang, Fabian Braun, Fabian Haas, Milagros N. Wong, Victor G. Puelles, Sydney E. Gies, Charlotte Meyer, Melanie Boerries, Martin Helmstädter, Oliver Kretz, Iris Hild, Eric Metzger, Roland Schüle, Wibke Bechtel-Walz, Tobias B. Huber
Figure 6
CRISPR/Cas9 LSD1 KO in human renal organoids leads to cyst formation.
