Pathophysiology of mesangial expansion in diabetic nephropathy: mesangial structure, glomerular biomechanics, and biochemical signaling and regulation

Abstract

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.

Keywords: Chronic kidney disease; Collagen accumulation; Diabetic kidney disease; Extracellular matrix; Glomerulus; Mesangial cell; Mesangial matrix; Mesangium; Renal fibrosis.

Fig. 1

Mesangial cell structure with its processes extending out to multiple capillaries. MC: mesangial cell, MM: mesangial matrix, P: podocytes, EC: endothelial cells, C: capillaries, GBM: glomerular basement membrane. The small arrows indicate the mesangial cell/GBM connections that oppose the hydrostatic pressures shown by long red arrow. The T-shaped marking indicates the mesangial cell process where the body of the T-shaped marking represents the axis of the mesangial processes, and the head of the T-shaped marking indicates the mesangial angles. The mesangial cell occupies a majority of the mesangium and is closely attached to the GBM directly by microfibrillar attachments or indirectly to the GBM via the mesangial matrix. The T-shaped mesangial processes are firmly embedded in between the capillaries and the GBM and enable the mesangial cell to maintain glomerular structure. Modified after [75] with permission

Fig. 2

A representation of the multiscale process that governs mesangial expansion from the molecular level (yellow) to the cellular level (orange) and tissue level (blue). Interactions between these different scales are important, especially the feedback influence of changes in mesangial matrix structure, composition, and stiffness on mesangial cell behavior. Ang II: angiotensin II, HG: hyperglycemia

Fig. 3

The role of the mesangial matrix in regulating mesangial cell phenotype, proliferation, and collagen accumulation. Structural and compositional alterations to the mesangial matrix cause the activation of the mesangial cell, which enhances proliferation and collagen I production. TGF- β production by the activated mesangial cell causes mesangial cell hypertrophy and prevention of mesangial cell proliferation. MC: mesangial cell, MM: mesangial matrix, TGF- β: transforming growth factor beta. Pointed arrows represent enhancement, and flathead arrows indicate inhibition