Nephrolithiasis is a significant source of morbidity, and its incidence has increased significantly over the last decades. This rise has been attributed to concurrent increasing rates of obesity, associated with a 3-time risk of developing NL. To date, the mechanism by which obesity is linked to stone formation has not been elucidated. We aimed to utilize a transcriptomics approach to discover the missing link between these two epidemic diseases. We investigated gene expression profiling of nephrolithiasis patients by two RNA-sequencing approaches: comparison between renal papilla tissue with and without the presence of calcified Randall's plaques (RP), and comparison between the papilla, medulla, and cortex regions from within a single recurrent stone forming kidney. Results were overlaid between differently expressed genes found in the patient cohort and in the severely lithogenic kidney to identify common genes. Overlay of these two RNA-sequencing datasets demonstrated there is impairment of lipid metabolism in renal papilla tissue containing RP linked to downregulation of fatty acid binding protein (FABP) 4. Immunohistochemistry of human kidney specimens and microarray analysis of renal tissue from a nephrolithiasis mouse model confirmed that FABP4 downregulation is associated with renal stone formation. In a FABP4 knockout mouse model, FABP4 deficiency resulted in development of both renal and urinary crystals. Our study revealed that FABP4 plays an important, previously unrecognized role in kidney stone formation, providing a feasible mechanism to explain the link between nephrolithiasis and metabolic syndrome.
Kidney international. 2020 Feb 29 [Epub ahead of print]
Kazumi Taguchi, Ling Chen, Manint Usawachintachit, Shuzo Hamamoto, Misun Kang, Teruaki Sugino, Rei Unno, David T Tzou, Benjamin A Sherer, Atsushi Okada, Takahiro Yasui, Sunita P Ho, Marshall L Stoller, Thomas Chi
Department of Urology, University of California, San Francisco, California, USA; Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Division of Biomaterials and Bioengineering, Department of Preventive and Restorative Dental Sciences, University of California San Francisco, San Francisco, California, USA., Department of Urology, University of California, San Francisco, California, USA; Division of Urology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Department of Urology, University of California, San Francisco, California, USA., Department of Urology, University of California, San Francisco, California, USA. Electronic address: .