7.3.2. Hypertension

The SHR model of essential hypertension in humans is widely used [132,133] and is characterized by an increase in BP and development of renal injury as age advances [126,133]. This model has been used to analyze the urinary enzymatic activities of APA, APN, and dipeptidyl peptidase-4 (DPP4) as biomarkers of renal injury in hypertension. These activities were measured in male SHR and WKY rats from the age of 2 to 8 months [134]. The SHR animals did not develop relevant signs of histopathological kidney alterations at the end of the study, but they showed increased glomerular area and cellularity. These activities were increased in monthly-collected urine samples from SHR rats and were correlated with systolic blood pressure throughout the study. Their increased activity in SHR animals indicate that a certain degree of tubular injury can be detected before the appearance of all histopathological manifestations of renal disease. These markers can therefore be used for the diagnosis of renal disease in early stages of hypertension and offer a non-invasive method to follow the progression of renal dysfunction in hypertension and other diseases.

## 7.3.3. Hyperthyroidism

In rats, hyperthyroidism is an endocrine disease associated with hypertension and renal abnormalities, accelerating the course of experimental hypertension, whereas hypothyroidism is associated with hypotension, preventing the development of hypertension and protecting against renal injury [135]. Ethanol-binding protein and N-acetyl-β-D-glycosaminidase, urinary biomarkers of tubular damage, are increased in hyperthyroid humans [136] and cats [137].

Our group studied the urinary excretion of APN, APA, CAP, and AspAp in control, hyperthyroid, and hypothyroid rats receiving a normal- or high-sodium diet. All APs were augmented in hyperthyroid rats, whereas their levels were similar between hypothyroid and control rats [138]. Hyperthyroid rats receiving a high sodium diet showed increased hypertension, cardiac/renal hypertrophy, albuminuria, and oxidative stress and a marked rise in urinary AP activities. AP activity was modestly elevated in the controls on a high-sodium diet but did not differ between hypothyroid rats on a high- versus normal-sodium diet. According to these results, the combination of T4 treatment and salt exert additive effects on the production of tubular damage, whereas hypothyroidism confers resistance to the effects of high salt intake on urinary AP activities. These findings support previous descriptions of hypothyroid status as beneficial in chronic kidney diseases [139]. It can be concluded that urinary AP activities are diagnostic biomarkers of renal injury in this experimental model. Our group [140] also determined APA activities in renal tissue and plasma samples from adult male euthyroid, hyperthyroid, and hypothyroid rats, and found a significantly higher expression of renal APA in hyperthyroid versus

control or hypothyroid rats. However, plasma APA activity was lower in hyperthyroid versus control rats, indicating that the increased APA in these animals is focalized in renal tissue.
