Psammomys obesus, a particularly important animal model for the study of the human diabetic nephropathy

Abstract

The Psammomys obesus lives in natural desert habitat on low energy (LE) diet, however when maintained in laboratory conditions with high energy (HE) diet it exhibits pathological metabolic changes resembling those of type 2 diabetes. We have evaluated and correlated the histopathology, metabolic and functional renal alterations occurring in the diabetic Psammomys. Renal function determined by measuring glomerular filtration rate (GFR), protein excretion, protein/creatinine ratio and morpho-immunocytochemical evaluations were performed on HE diet diabetic animals and compared to LE diet control animals. The diabetic animals present a 54% increase in GFR after one month of hyperglycemic condition and a decrease of 47% from baseline values after 4 months. Protein excretion in diabetic animals was 5 folds increased after 4 months. Light microscopy showed an increase in glomeruli size in the diabetic Psammomys, and electron microscopy and immunocytochemical quantitative evaluations revealed accumulation of basement membrane material as well as frequent splitting of the glomerular basement membrane. In addition, glycogen-filled Armanni-Ebstein clear cells were found in the distal tubules including the thick ascending limbs of the diabetic animals. These renal complications in the Psammomys, including changes in GFR with massive proteinuria sustained by physiological and histopathological changes, are very similar to the diabetic nephropathy in human. The Psamommys obesus represents therefore a reliable animal model of diabetic nephropathy.

Keywords: Diabetic nephropathies; Glycogen nephrosis; Psammomys.

Fig. 1

Glomerular filtration rate (GFR) of the control low energy (LE) diet and the diabetic high energy (HE) diet Psammomys after 4, 8, 12, and 16 weeks. Data are presented as means±SE. P<0.005 vs. controls animals.

Fig. 2

Histology of representative glomeruli from the diabetic (high energy diet) Psammomys at the beginning of the diet (time 0) and at 8 and 16 wk. Glomeruli area gradually increased in 8 and 16 weeks compared to time 0 (×300). Quantitative data appear in Table 3.

Fig. 3

(A, B) PAS staining of sections of kidneys from control (low energy [LE] diet) and the diabetic (high energy [HE] diet) Psammomys after 16 wk of feeding with the appropriate diet (×200). C, clear cells.

Fig. 4

Renal distal tubules. Epithelial cells of the control (low energy [LE] diet) (A) and a diabetic (high energy [HE] diet) (B) animals. In (A) the cytoplasm (cyt) appears normal with its different components, while in (B), the clear cell is filled by glycogen (gly) which was extracted during tissue preparation (×15,000). The cell cytoplasm appears clear; m, mitochondria; mv, microvilli; N, nucleus.

Fig. 5

Electron micrographs of the glomerular wall of a control (low energy diet) (A) and of a diabetic (high energy diet) (B) animals. For the control animal (A) the glomerular wall appears normal with a thin glomerular basement membrane (GBM) between the endothelial cell (End) and the podocyte (P). On the other hand, for the diabetic animal (B), the GBM, shows sites of increase thickness and material deposition (^*) as well as sites where the GBM splits in two (long arrows) (×30,000). Small arrows, slit diaphragm. CL, capillary lumen; US, urinary space.

Fig. 6

(A, B) Immunocytochemical detection of endogenous serum albumin by the protein A- gold technique. Glomerular walls of a control (A) and a diabetic animal (B). The gold particles reveal that serum albumin antigenic sites are present in large amounts over the capillary lumen (CL) and over the glomerular basement membrane (GBM). In the control animals (A), the labeling appears to be mainly on the endothelial side of the basement membrane, and no gold particles are seen in the urinary space (US). Arrow: slit diaphragm. For the diabetic animal (B), the labeling over the GBM appears to be distributed throughout the GBM and we can detect dense labeled areas in the urinary space (arrowheads) (×40,000). P, podocyte; End, endothelial cell. (C) Distribution of serum albumin immunolabeling across the glomerular wall as expressed over ratio values (R). In the control animals the distribution is asymmetrical, demonstrating that most of the albumin is retained on the endothelial side of the glomerular basement membrane. The distribution for the diabetic animals is more uniform across the basement membrane indicating alteration in the passage of albumin across the glomerular wall.