Hemin attenuates cisplatin-induced acute renal injury in male rats

Abstract

Background: The aim of this study is to investigate the protective effects of hemin (the heme oxygenase-1 [OH-1] inducer) against nephrotoxic effects induced by cisplatin [cis-diamminedichloroplatinum II (CP)] in male rats.

Methods: The evaluation was performed through monitoring renal redox parameters: lipid peroxidation (LPO), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GR), and reduced glutathione (GSH). The work also examined renal function tests (urea and creatinine), tissue proinflammatory mediator like nitric oxide (NO), and kidney cytopathology.

Results: A single intraperitoneal dose of CP (10 mg/kg b.w.) caused significant elevation of blood urea, serum creatinine, and renal LPO and NO, along with significant decline of the activities of GPx and GR, but renal SOD activity and GSH level were statistically insignificant as compared to control group. Subcutaneous injection of hemin (40 µmol/kg b.w.) partially ameliorated CP-induced renal damage, based on suppression of blood urea, serum creatinine, the renal MDA and NO levels, and increased antioxidant capacity in CP-treated rats. The results of histopathological and ultrastructural investigations supported the renoprotective effect of hemin against CP-induced acute toxicity.

Conclusion: The induction of HO-1 by hemin is a promising approach in the treatment of CP-induced nephrotoxicity. However, further preclinical studies are warranted to test effectiveness of CP/hemin on the outcome of tumor chemotherapy.

Figure 1

Photomicrographs of rat kidney. (a) Control group: normal histological structure. ((b)-(c)) CP group: severe glomerular congestion (∗, in (b)), glomerular atrophy (arrow, in (c)) and dilatation of Bowman's space (bs, in (c)), and degeneration of renal tubular cells (dg, in (b) and (c)). (d) CP plus hemin group: mild tubular degeneration (arrow), a normal-looking glomerulus (g) is also discernible. (e) Hemin group: renal histology is comparable to control.

Figure 2

Electron micrographs of kidney of control rats. (a) Note the glomerulus has podocytes (P) which remain in contact with GBM by foot processes (arrows). The glomerular capillaries (Cap) are lined by endothelial cells (E) which are richly fenestrated and supported by mesangial cells (MCs) with their surrounding extracellular matrix. (b) Proximal tubules have well-developed brush border microvilli (BBM), and their lining epithelia contain large number of mitochondria (with normal feature) (M), few lysosomes (Ly), and many basal infoldings (F), N: nucleus. (c) Epithelial lining of distal tubule with apical nuclei (N), numerous mitochondria (M), short cisternae of rough endoplasmic reticulum, and few microvilli toward the lumen (L).

Figure 3

Electron micrographs of kidney of CP-treated rats. (a) Renal glomerulus with thickened GBM (++), capillary lumens are obliterated by endocapillary hypercellularity and hypertrophy (arrows). Note also fusion of secondary foot processes (FP) and mesangial hypercellularity (arrowheads). (b) Proximal convoluted tubule cell containing large cytoplasmic vacuoles (V), clusters of deformed mitochondria (arrows), numerous lysosomal bodies (Ly), and lamellar (myeloid) body (Mb). Observe nucleus (N) with condensed chromatin pattern. Arrowhead points to partial destruction of the brush border. (c) Abnormal distal tubular cells with few organelles. Arrow indicates apoptotic cell.

Figure 4

Electron micrographs of kidney of CP plus hemin-treated rats. (a) Glomerulus with nearly regular foot processes (arrows) and limited mesangial matrix (∗). Arrowhead indicates a resting platelet inside glomerular capillary vessel. Capillary endothelium (E) and slight thickening of GBM (++) are indicated. (b) Proximal convoluted tubule cell showing loss of large vacuolar structures; only small vacuoles (V) are seen beneath the intact brush border microvilli (BBM). Nucleus (N), mitochondria (M), and lysosomes are of normal morphology. (c) Dilated distal tubule with normal cellular ultrastructure. Detachment/loss of pleomorphic microvilli is indicated by arrow.