Effect of angiotensin II type 1 receptor blocker on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats

Abstract

Objective: To study the possible effect of angiotensin II type 1 Receptor blocker (AT1 blocker) on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. Forty five rats were divided randomly into a control (group I), group II, received cadmium chloride at a dose of 5 mg/kg/day, orally, for nine weeks, group III received telmisartan (TEL) treatment (1 mg/kg/day, orally) one week before cadmium administration and continued for ten weeks.

Results: Telmisartan significantly reduced blood urea nitrogen (BUN) and serum creatinine levels which were increased significantly by cadmium. Telmisartan significantly suppressed lipid peroxidation, compensated deficits in the antioxidant defenses (super oxide dismutase (SOD) level and catalase activity), decreased the elevations of nitric oxide (NO) and cadmium ion concentrations in renal tissue observed in Cd-treated rats. Group III had a significant decrease of urinary levels of total protein, N-acetyl-β-d-glucosaminidase (NAG), alkaline phosphatase (ALP) and γ-glutamyl-transpeptidase (GGT) and urinary 8-isoprostanes than those of group II. Telmisartan decreased the systolic blood pressure significantly than those of group II. Histopathological examination revealed that cadmium-induced renal tissue damage was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the cadmium-induced overexpression of parathyroid hormone receptor 1 (PTHR1) in renal tissue. RT-PCR analysis showed that Cd increased renal expression of PTHrP; however telmisartan could decrease the expression of PTHrP in group III.

Conclusion: Blocking AT1 receptors significantly decreases PTHrP over expression and ameliorates renal dysfunction in Cd induced nephrotoxicity. These data suggest that Ang II might contribute to pathophysiology and deleterious effects in cadmium nephrotoxicity.

Keywords: Cadmium; nephrotoxicity; parathyroid hormone related protein; telmisartan.

Figure 1

Systolic BP (A) and proteinuria (B) in control, group II and group III. Data are shown as mean ± SD. *P<0.05, ***P<0.001 versus control; ##P<0.01 versus group II.

Figure 2

Effect of telmisartan treatment on serum and renal tissue levels of Angiotensin II of rats treated with cadmium for nine weeks. Values are mean ± SD. *p<0.05, **p<0.01 and ***p<0.001 as compared to control group. ##p<0.01 and #p<0.05 as compared to group II.

Figure 3

A. Representive photomicroscopy of a section in the kidney of a control rat showing the renal corpuscle with the parietal layer of Bowmman’s capsule (arrow head). glomerular and normal Bowmann’s space (*). Normal appearance of the proximal (P) and distal (D) in control convulated tubules. B. Group II showing apparent glomerular atrophy (G) with widened Bowman’s space (*). Swelling of the renal tubules is observed (thick arrows). The proximal tubules showed marked vaculation of the cytoplasm (+), some nuclei in the proximal tubules appear pyknotic (arrow head) or karyolsed (thin rrow) and others show exfoliation (tailed arrow). C. Group III showing swelling of the renal tubules (thick arrows) and some proximal tubules showed pyknotic nuclei (arrow head). (H&E) X 400. Bar = 50 μm.

Figure 4

Immunohistochemical staining of sections from rat kidneys (X400). A. Normal expression of PTHR1 in the tubular epithelium of group I The glomerulus showed no positivity for PTHR1. B. Marked activation of PTHR1 (highly positive reaction) in the proximal tubules (P) by cadmium intake to adult male rats of group II for nine weeks. C. The detection of PTHR1 in the renal tissues of group III demonstrates a weak positivity slightly higher than the control group. Bar = 50 μm.

Figure 5

Representative graph corresponding to PTHrP mRNA changes (evaluated by RT-PCR) in the kidney of all studied groups. A. Telmisartan treatment decreased PTHrP mRNA in renal tissues of group III. B. PhosphorImager analysis of RT-PCR amplification using specific oligonucleotide primers for PTHrP mRNA in the kidney of control, group II and group III. Total RNA isolated from all Kidneys was used for RT-PCR reactions as described in Materials and Methods. Lane 1 from the left is the 1-kb ladder control; lane 2: group I, lanes 3: group II, and 4: group III correspond to the primers specific for PTHr-P at 266 bp. GAPDH mRNA was included as a constitutive control. *p<0.05,***p<0.001 as compared to control group. ##p<0.01 as compared to group II.