Urinary angiotensinogen increases in the absence of overt renal injury in high fat diet-induced type 2 diabetic mice.

Aim Of The Study: During type 2 diabetes (T2D) and hypertension there is stimulation of renal proximal tubule angiotensinogen (AGT), but whether urinary excretion of AGT (uAGT) is an indicator of glomerular damage or intrarenal RAS activation is unclear. We tested the hypothesis that elevations in uAGT can be detected in the absence of albuminuria in a mouse model of T2D.

Methods: Male C57BL/6 mice (N = 10) were fed a high fat (HFD; 45% Kcal from fat) for 28 weeks, and the metabolic phenotype including body weight, blood pressures, glucose, insulin, ippGTT, HOMA-IR, and cholesterol was examined. In addition, kidney Ang II content and reactive oxygen species (ROS) was measured along with urinary albumin, creatinine, Ang II, and AGT.

Results: All parameters consistent with T2D were present in mice after 12-14 weeks on the HFD. Systolic BP increased after 18 weeks in HFD but not NFD mice. Intrarenal ROS and Ang II concentrations were also increased in HFD mice. Remarkably, these changes paralleled the augmentation uAGT excretion (3.66 ± 0.50 vs. 0.92 ± 0.13 ng/mg by week 29; P < 0.01), which occurred in the absence of overt albuminuria.

Conclusions: In HFD-induced T2D mice, increases in uAGT occur in the absence of overt renal injury, indicating that this biomarker accurately detects early intrarenal RAS activation.