Associations between structural and functional changes to the kidney in diabetic humans and mice

Abstract

Type 1 and Type 2 diabetic patients are at high risk of developing diabetic nephropathy (DN). Renal functional decline is gradual and there is high variability between patients, though the reason for the variability is unknown. Enough diabetic patients progress to end stage renal disease to make diabetes the leading cause of renal failure. The first symptoms of DN do not appear for years or decades after the onset of diabetes. During and after the asymptomatic period structural changes develop in the diabetic kidney. Typically, but not always, the first symptom of DN is albuminuria. Loss of renal filtration rate develops later. This review examines the structural abnormalities of diabetic kidneys that are associated with and possibly the basis for advancing albuminuria and declining GFR. Mouse models of diabetes and genetic manipulations of these models have become central to research into mechanisms underlying DN. This article also looks at the value of these mouse models to understanding human DN as well as potential pitfalls in translating the mouse results to humans.

Keywords: Diabetic nephropathy; Glomerulus; Mouse models; Renal morphology; Transgenic mice.

Figure 1. Approximate periods of normalbuminuria, microalbuminuria or macroalbuminuria in humans diabetes (A) or in mouse experimental models of diabetes (B)

The time scale on top is years from the onset of diabetes. The bars show the period of time after diabetes onset when more than 10% of diabetics exhibit normalbuminuria (open bars), microalbuminuria (dotted bars) or macroalbuminuria (solid bars). Figure A is derived from studies on Type 1 and 2 diabetes in humans (Adler, Stevens, 2003, DCCT, 1995, Remuzzi, Benigni, 2006). It should be noted that the majority of human diabetics do not develop DN in 20 years. Figure B is derived from studies of Type 1 and 2 models of diabetes in mice (Qi, Fujita, 2005, Susztak, Bottinger, 2004, Zhao, Wang, 2006, Zheng, Noonan, 2004). Essentially 100% of experimental diabetic mice develop early signs of DN within 2 months of diabetes.

Figure 2. Few tubules stain for albumin in mice and humans with diabetic nephropathy

Panel A shows a kidney section from an albuminuric OVE26 diabetic mouse stained by immunohistochemistry for mouse albumin (40X magnification). The arrow indicates the same albumin stained tubules which are magnified at 400X magnification in Panel B. Panel C is a needle biopsy sample stained for human albumin from a diabetic patient. Panels D–F are non-diabetic samples that correspond in species, staining and magnification to the diabetic sample shown in the panel immediately above.

Figure 3. Trichrome stained glomeruli obtained by needle biopsy from nondiabetic (A) and diabetic (B) patients

The diabetic glomerular tuft is enlarged due in part to expanded mesangial matrix. The diabetic sample demonstrates acellular nodular sclerosis (arrow) as well as periglomerular and interstitial fibrosis (**). Open capillary loops in the normal sample (*) are rare in the diabetic sample. Magnification 400X.