Glomerulopathy in spontaneously obese rhesus monkeys with type 2 diabetes: a stereological study

Abstract

Background Animal models provide insights into the diabetic nephropathy pathogenesis, however, available rodent models do not mirror the heterogeneity of lesions in type 2 diabetic (T2DM) patients, and do not progress to end stage renal disease. Previous studies showed that spontaneously obese T2DM rhesus monkeys develop many of the features of human diabetic glomerulopathy, and may progress to ESRD. Here, in order to further characterize diabetic glomerulopathy in this model, we used electron microscopic stereology.. Methods Renal biopsies from 17 diabetic, 17 pre-diabetes/metabolic syndrome (preDM/MS) and 11 non-diabetic monkeys were studied. Fractional volumes of mesangium [Vv(Mes/glom)], mesangial matrix [Vv(MM/glom)] and mesangial cells [Vv(MC/glom)], glomerular basement membrane (GBM) width and peripheral GBM surface density per glomerulus [Sv(PGBM/glom)] were estimated. Glomerular filtration (GFR) and albumin excretion rates (AER) were measured in a limited number of animals. Glomerular structural and biochemical/metabolic data were compared among the groups. Results Diabetic monkeys showed classical diabetic nephropathy changes, including GBM thickening (p=0.001), increased Vv(Mes/glom) (p=0.02), and reduced Sv(PGBM/glom) (p=0.03) compared to non-diabetic monkeys. Increased Vv(Mes/glom) was primarily due to increased Vv(MM/glom) (p=0.03). Glomerular structural parameters inter-relationships in diabetic monkeys mirrored those of human diabetic glomerulopathy. AER was greater (p=0.03) in diabetic vs. non-diabetic monkeys. There was evidence for a positive relationship between AER and Vv(Mes/glom). Conclusions These studies indicate that this primate model shares many features of human diabetic glomerulopathy. Mesangial expansion in this model, similar to human diabetic nephropathy and different from available rodent models of the disease, is primarily due to increased mesangial matrix.

Proteinuria in Cynomolgus macaques (Macaca fascicularis) with Spontaneously Developed Metabolic Disorder and Diabetes: Transcriptome Analysis of Biopsy Kidney

“…Using this criteria, none of the normal monkeys had positive Ualbumin, only 1 pre-DM>42 mg; 2 DM with micro-albuminuria and 7 DM with diabetic nephropathy, a distribution highly concentrated in the DM group (45%). This observation is consistent with the report by Najafian et al in spontaneously developed obese, dysmetabolic and diabetic rhesus monkeys [22].…”

“…With the average body weight just ~1/10 in the cynomolgus monkeys (5-15 kg) compared to human (~75 kg), proportionally, it is reasonable to set Ualbumin at 8-20 mgfor micro-albuminuria and >20 mg for diabetic nephropathy. Although somewhat arbitrary, this criterion, however, fits to the characterization of the monkey colonies in the present and other studies [22]. Using this criteria, none of the normal monkeys had positive Ualbumin, only 1 pre-DM>42 mg; 2 DM with micro-albuminuria and 7 DM with diabetic nephropathy, a distribution highly concentrated in the DM group (45%).…”

Transplantation of Bone Marrow Mesenchymal Stem Cells for the Treatment of Type 2 Diabetes in a Macaque Model

“…The pharmacological efficacy of treatment in preclinical evaluations performed on monkeys has more relevance for human health than any other species of experimental animals. Monkeys also spontaneously develop T2DM [Najafian et al, 2011]. Therefore, the macaque is an ideal disease model for human T2DM.…”

A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract

“…Some reports also showed no difference with the insulin and C-peptide between spontaneously diabetic and non-diabetic monkeys, 16,27 but some reports are contradictory. 15,23,[28][29][30] The primary reason is likely that the insulin maintains normal at early stage of T2DM, whereas it increases to compensate the insulin resistance later and ultimately decreases or does not express because of β-cells dysfunctions. 29 The concentrations of fasting insulin also depend on age.…”

“…Significantly, spontaneous NHPs model, in a way, is a more valuable resource for understanding the mechanism and exploring the intervention, because it imitates a natural processes of diabetic or hyperglycaemic in a large proportion of patients and may stabilize the phenotypes once in morbidity. It has been found that spontaneous hyperglycaemic macaques developed nephropathy, 15 retinal denaturation, 16 cardiomyopathy, 17 cardiac dysfunction, 18 α‐synuclein deposition 9 and age‐dependent amyloid‐β (Aβ) pathology, 19–21 which partly is consistent with diabetic or chronic hyperglycaemic patients who may suffer from diabetic kidney disease, diabetic retinopathy, cardiovascular disease, Parkinson's disease (PD) and Alzheimer's disease (AD).…”