A new era in nephrology: the role of super-resolution microscopy in research, medical diagnostic, and drug discovery

Abstract

For decades, electron microscopy has been the primary method to visualize ultrastructural details of the kidney, including podocyte foot processes and the slit diaphragm. Despite its status as the gold standard, electron microscopy has significant limitations: it requires laborious sample preparation, works only with very small samples, is mainly qualitative, and is prone to misinterpretation because of section angle bias. In addition, combining imaging and protein staining with antibodies poses a challenge, limiting electron microscopy’s integration into routine research and diagnostic workflows. As imaging technology advances, super-resolution microscopy, with an optical resolution below 100 nm, presents a promising alternative for detailed insights into glomerular ultrastructure. This review explores various super-resolution techniques, particularly 3-dimensional structured illumination microscopy, and demonstrates how they can be applied to standard histological sections. The 3-dimensional structured illumination microscopy–based measurement procedure—podocyte exact morphology measurement procedure—offers a novel approach to quantifying podocyte foot process morphology and can detect podocyte foot process changes even before proteinuria is present. Furthermore, the podocyte exact morphology measurement procedure can be combined with mRNA detection, multiplex staining, and deep learning algorithms, making it a powerful tool for kidney research, preclinical studies, and personalized diagnostics. This advancement has the potential to accelerate drug development and enhance therapeutic precision, heralding a new era of high-precision nephrology.