Diabetic Nephropathy: A Review on Pathological Relevant Models

Diabetic nephropathy (DN) is one of the severest micro-vascular complications of diabetes mellitus and it becomes the primary inducement of end-stage renal disease (ESRD) in the world. Although the pathophysiology of DN has been widely addressed, therapeutic measures are restricted, mainly due to the complexity of genetic, metabolic, and hemodynamic cross-links that may exist in this condition. Here we present an overview of the most recent in vivo and in vitro models adopted for detection of DN, discussing the advantages, limitations, and applications of each model. The paper systematically clusters animal models into surgical, chemical, viral, genetic, and gestational approaches, and covers the advent of state-of-the-art organ-on-chip (OOC) technologies. Surgical models including nephrectomy are more comparable to human renal injury, but are restricted by ethical considerations and species differences. Chemical models that mimic it, such as those produced by streptozotocin (STZ), are reproducible and easy to use, but are limited as more often than not they do not truly recapitulate the situations in human DN. Genetic models allow for specific control of disease pathways, but are expensive and may miss effects of factors in the environment. Furthermore, gestational models provide important insights pertaining to transgenerational risks and maternal-fetal interactions. Recent advances in OOC systems provide one such alternative, by enabling an approach that combines physiological relevance with human cells, thereby reducing animal use and facilitating HTS. In addition, the review highlights the advantages of animal models, including the convenience of studying whole-organism responses, systemic effects, and chronic disease that are challenging to recapitulate in vitro. Yet it also identifies the constraints that require additional methods. Taken together, the review emphasizes the necessity to adopt integrated model systems for more precise and comprehensive interpretation of DN toward the rapid discovery of effective therapeutics.