Progression of diabetic kidney disease in T2DN rats

Abstract

Diabetic kidney disease (DKD) is one of the leading pathological causes of decreased renal function and progression to end-stage kidney failure. To explore and characterize age-related changes in DKD and associated glomerular damage, we used a rat model of type 2 diabetic nephropathy (T2DN) at 12 wk and older than 48 wk. We compared their disease progression with control nondiabetic Wistar and diabetic Goto-Kakizaki (GK) rats. During the early stages of DKD, T2DN and GK animals revealed significant increases in blood glucose and kidney-to-body weight ratio. Both diabetic groups had significantly altered renin-angiotensin-aldosterone system function. Thereafter, during the later stages of disease progression, T2DN rats demonstrated a remarkable increase in renal damage compared with GK and Wistar rats, as indicated by renal hypertrophy, polyuria accompanied by a decrease in urine osmolarity, high cholesterol, a significant prevalence of medullary protein casts, and severe forms of glomerular injury. Urinary nephrin shedding indicated loss of the glomerular slit diaphragm, which also correlates with the dramatic elevation in albuminuria and loss of podocin staining in aged T2DN rats. Furthermore, we used scanning ion microscopy topographical analyses to detect and quantify the pathological remodeling in podocyte foot projections of isolated glomeruli from T2DN animals. In summary, T2DN rats developed renal and physiological abnormalities similar to clinical observations in human patients with DKD, including progressive glomerular damage and a significant decrease in renin-angiotensin-aldosterone system plasma levels, indicating these rats are an excellent model for studying the progression of renal damage in type 2 DKD.

Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats

“…Here, we characterized sexual dimorphism, glucose homeostasis, and renal function in a model of non-obese type diabetic rats with the spontaneous development of advanced diabetic nephropathy (T2DN rats). This rodent model displays similar renal abnormalities and hyperglycemic levels seen in humans with the disease (23, 35,38,49). Our results indicate that both sexes developed nonobese T2DM phenotypes, where females had significant protection from the development of severe forms of DKD.…”

Scanning ion conductance microscopy of live human glomerulus

“…Our data revealed a significant loss of podocyte foot processes in T2DN glomeruli providing an accurate evaluation for histopathological changes occurred in diabetic nephropathy that underlie nephrinuria and albuminuria in these rats. 15 Here, for the first time, we demonstrated a successful approach in assessing the three-dimensional surface structure of freshly isolated, live human glomerulus. Human renal glomeruli are spherical structures with a diameter of around 300 µm 16 ; thus, the tip of the pipette must carefully approach the top of the region of interest.…”

Role of opioid signaling in kidney damage during the development of salt-induced hypertension

“…The dynamic changes in podocyte cytoskeletal remodeling during opioid treatment were visualized by super-resolution hopping probe ion-conductance microscopy, an advanced three-dimensional topographical ersion of SICM. The identification of podocyte lamellipodial protrusions was carried out using the custom-modified scanner ICNano (ICAPPIC), as previously described ( Novak et al, 2009 ; Palygin et al, 2019 ). The sample was manually positioned in the x–y directions under an optical microscope, and the scanning pipette was positioned in the z-direction with a piezoelectric actuator.…”

“…Slides were stained with Masson's trichrome stain. A double-blind glomerular injury score was assessed using a 0-4 scale, as previously described (Palygin et al, 2019). Immunohistochemical staining of κ-OR protein in human kidneys was visualized with κ-OR-1 antibody (KOR-1 (D-8), 1:50, #sc-374479; Santa Cruz Biotechnologies).…”