Diabetic nephropathy, a kidney complication arising from diabetes, is the leading cause of death in diabetic patients. Unabated, the growing epidemic of diabetes is increasing instances of diabetic nephropathy. Although the main causes of diabetic nephropathy have been determined, the mechanisms of their combined effects on cellular and tissue function are not fully established. One of many damages of diabetic nephropathy is the development of fibrosis within the kidneys, termed mesangial expansion. Mesangial expansion is an important structural lesion that is characterized by the aberrant proliferation of mesangial cells and excess production of matrix proteins. Mesangial expansion is involved in the progression of kidney failure in diabetic nephropathy, yet its causes and mechanism of impact on kidney function are not well defined. Here, we review the literature on the causes of mesangial expansion and its impacts on cell and tissue function. We highlight the gaps that still remain and the potential areas where bioengineering studies can bring insight to mesangial expansion in diabetic nephropathy.

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Diabetic kidney disease (DKD) is a growing health problem that affects a significant portion of the global population. With a rising global patient number of over 135 million and a yearly incident case of over 2 million, the burden of DKD is rising. Glomerular fibrosis is tissue damage that occurs within the kidney of DKD patients for which effective therapeutic treatments are lacking. One of the reasons for the lack of therapeutic efficacy is glycemic memory where even after blood glucose within diabetic patients is regulated, glomerular fibrosis due to the initial high blood glucose continues to progress. This phenomenon is readily observed in diabetic patients who receive pancreatic transplant for blood glucose regulation where the glomerular fibrosis takes 10 years for full recovery to be observed. In pursuit of determining why it takes a long time for glomerular fibrosis to be reversed, we developed a mechanistic systems biology model of glomerular fibrosis in diabetes from a previous model of interstitial fibrosis. The adapted model consists of a system of ordinary differential equations that models the complex disease etiology and progression of glomerular fibrosis in diabetes. Within the scope of the mechanism we incorporated, we found that advanced glycation end products, which are matrix proteins that are modified due to high blood glucose, are the reason for the delay in the recovery of glomerular fibrosis. The idea that advanced glycation end products are one of the key mediators of glycemic memory is well known in the broad scope of diabetes and its many complications. The mechanism for how advanced glycation end products cause a delay in the recovery of glomerular fibrosis, however, is less established. Following that, the mechanism for why therapeutics targeting glycemic memory such as aminoguanidine, and alagebrium lack efficacy is also not well established. Using our model, we postulate that glucose control, and aminoguanidine are not effective because they do not remove accumulated advanced glycation end products. Further, our model predicts that treatments breaking down advanced glycation end products, such as alagebrium, would be the most efficacious at reversing glomerular fibrosis. Our model helps explain the lack of efficacy of alagebrium at treating advanced glomerular fibrosis due to the inability of alagebrium to reduce TGF-β. There is a well-known therapeutic treatment efficacy reduction when treatment is applied to advanced glomerular fibrosis compared to early glomerular fibrosis. We postulate that two different mechanisms associated with short lived advanced glycation end products and long-lived advanced glycation end products can explain the difference in the response to treatment of glomerular fibrosis when treatment is applied to early glomerular fibrosis vs advanced glomerular fibrosis. Using our systems biology model, we illuminate mechanistic understanding of disease etiology of glomerular fibrosis in diabetes, and then we provide mechanistic explanations for the lack of efficacy of different pharmacological agents at treating glomerular fibrosis. This understanding can enable the development of therapeutics that are more efficacious at treating kidney damage in diabetes.