Temporal Profile of Diabetic Nephropathy Pathologic Changes

Abstract

Diabetic nephropathy, by far, is the most common cause of end stage renal disease in the US and many other countries. In type 1 diabetes, the natural history of diabetic nephropathy is tightly linked to evolution of classic lesions of the disease, namely glomerular basement membrane thickening, increased mesangial matrix, and reduced glomerular filtration surface density. These lesions progress in parallel and correlate with increased albumin excretion rate and reduced glomerular filtration rate across a wide range of renal function. In fact, the vast majority of the variances of albumin excretion and glomerular filtration rates can be explained by these glomerular lesions alone in type 1 diabetic patients. Although, classic lesions of diabetic nephropathy, indistinguishable from those of type 1 diabetes, also occur in type 2 diabetes, renal lesions are more heterogeneous in type 2 diabetic patients with some patients developing more advanced vascular or chronic tubulointerstitial lesions than diabetic glomerulopathy. More research biopsy longitudinal studies, especially in type 2 diabetic patients, are needed to better understand various pathways of renal injury in diabetic nephropathy.

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

“…It was found for the first time in this study that inflammation significantly increased lipid accumulation in the tubulointerstitium of db/db mice; however, we did not observe a difference in the plasma lipid profiles between the control and inflammation group, which might be explained by the lipid redistribution induced by inflammation. Ruan et al [15] and our group [27][28][29][30][32][33][34][35] demonstrated that inflammation induced lipid redistribution. In response to inflammation, lipid redistribution and accumulation in tissues might occur at several levels and sites: from circulation to tissue, from tissue to tissue, and from organelle to organelle [15] .…”

“…In peripheral tissues, inflammation induced an increase in cholesterol uptake, a decrease in cholesterol efflux and an increase in endogenic cholesterol synthesis. Our previous studies also showed that inflammatory stress exacerbated lipid accumulation in hepatic cells and vas-cular smooth muscle cells as well as multiple organs of db/db mice [27][28][29] . We also have revealed that inflammation-induced lipid deposition accelerated podocyte injury of db/db mice, which was mediated by dysregulation of LDLr [30,31] .…”

Molecular mechanisms of diabetic kidney disease

“…Glomerular basement membrane (GBM) thickening (above the age-expected limits) is the earliest electron microscopical lesion observed in patients with DKD (8)(9)(10). Mesangial expansion, caused by cell enlargement and their increased matrix secretion, is the most commonly observed histopathological lesion by light microscopy.…”

Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?

“…Primarily due to expansion of the lamina densa, GBM thickening in diabetes is diffuse and quite uniform (Fig. 1B) (142). Thought to result from an imbalance between the synthesis and degradation of mostly normal ECM constituents, GBM thickening has been reported in patients in the preclinical stage of diabetes, so-called “prediabetes” (99).…”