Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate-salt hypertensive uni-nephrectomized KKAy mice.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-ß). Moreover, compound A significantly suppressed TGF-ß-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.

Antihyperlipidemic effect of Melothria maderaspatana leaf extracts on DOCA-salt induced hypertensive rats.

OBJECTIVE: To investigate the antihyperlipidemic effect of crude ethanolic extract of Melothria maderaspatana (M. maderaspatana) leaf (CEEM) on deoxycorticosterone acetate (DOCA)-salt hypertensive rats. METHODS: A midscapular incision was made on each rat and the left kidney was excised after ligation of the renal artery. The surgical wound was closed using an absorbable suture. After one week recovery period, hypertension was induced by subcutaneous injection of DOCA-salt solution, twice a week, and the rats received a 1% sodium chloride solution as drinking water throughout the experimental period. CEEM or nifedipine was administered orally once a day for 6 weeks. RESULTS: In DOCA-salt hypertensive rats, the level of plasma and tissues of total cholesterol (TC), triglycerides (TG), free fatty acids (FFA) and phospholipids (PL) significantly increased and administration of CEEM significantly reduced these parameters towards normality. Further, the levels of low density lipoprotein-cholesterol (LDL-C) and very low density lipoprotein-cholesterol (VLDL-C) significantly increased while high density lipoprotein-cholesterol (HDL-C) decreased in hypertensive rats and administration of CEEM brought these parameters to normality which proved their antihyperlipidemic action. Histopathology of liver, kidney and heart on DOCA-salt induced rats treated with CEEM showed reduced the damages towards normal histology. CONCLUSIONS: These findings provided evidence that CEEM was found to be protecting the liver, kidney and heart against DOCA-salt administration and the protective effect could attribute to its antihyperlipidemic activities.