Role of Protein Misfolding in Human Kidney Diseases

Sebastián Jaurreteche^1,2,*, María Luana Brajkovic², María Victoria Del Rosal², Graciela Venera³, Carlos Daniel De La Vega Elena⁴
1 Uro-Onco-Nephrology and Transplant, Sanatorio Parque SA-Grupo Oroño, 860, Rosario, Z.C. 2000, Argentina
2 Biophysics and Human Physiology, School of Medicine, Instituto Universitario Italiano de Rosario, Rosario, Z.C. 2000, Argentina
3 Research Department, Instituto Universitario Italiano de Rosario, Rosario, Z.C. 2000, Argentina
4 Instituto de Investigaciones, Instituto Universitario Italiano de Rosario, Rosario, Z.C. 2000, Argentina
* Corresponding Author: Sebastián Jaurreteche. Email: email

BIOCELL https://doi.org/10.32604/biocell.2026.073790

Received 25 September 2025; Accepted 04 January 2026; Published online 21 January 2026

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Abstract

Protein misfolding has emerged as a central mechanism in the pathogenesis of human kidney diseases. Normally, proteins achieve their native conformation through highly regulated folding processes in the endoplasmic reticulum (ER) and cytoplasm, assisted by molecular chaperones and quality-control pathways. However, genetic variants, environmental stressors, or cellular overload can destabilize this system, resulting in unfolded or misfolded proteins that trigger aggregation, amyloid formation, endoplasmic reticulum stress, and activation of the unfolded protein response (UPR). These events may ultimately lead to loss of function, gain of toxic function, and apoptosis. This review summarizes the structural basis of protein folding and the mechanisms by which misfolding disrupts renal homeostasis. Special emphasis is given to amyloidogenic pathways and to the contribution of UPR and ER-associated degradation in maintaining proteostasis. We analyze key renal diseases in which protein misfolding plays a causal or contributory role, including amyloidosis, Fabry disease, von Hippel–Lindau syndrome, uromodulin related autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD-related), Alport syndrome, congenital nephrotic syndrome, diabetic nephropathy, and nephrogenic diabetes insipidus. We also highlight emerging associations in chronic kidney disease and glomerulopathies. Finally, therapeutic strategies directly targeting protein misfolding are reviewed, such as pharmacological chaperones, proteostasis enhancers, and gene-editing approaches. Understanding the interplay between protein misfolding and renal pathology. It has translational medical significance, as it may be the future direction towards personalized medicine and/or combination therapies, not only clarifies disease mechanisms but also provides opportunities for innovative, mechanism-based treatments. This study aimed to review current knowledge regarding the role of protein misfolding in human kidney diseases, with the aim of evaluating current therapies available and which mechanisms of protein misfolding could be translated into clinical practice as future therapeutic targets.