Masuhisa Nakamura

Nephrotoxicity of a new platinum compound, 254-S, evaluated with rat kidney cortical slices

The addition of a new compound containing platinum, 254-S, an antineoplastic agent, to medium had no effect on p-aminohippurate (PAH) accumulation, gluconeogenesis, or potassium and ATP concentrations in rat kidney cortical slices at the concentrations tested, up to 10 mM. At 1 mM, cisplatin, used for comparison, significantly decreased all of these biochemical indices in the slices. Administration of 254-S at a low dose (10 mg/kg i.v.) to rats decreased the ability of the slices to accumulate PAH and to maintain the potassium concentration, without affecting levels of urea or creatinine in blood plasma. 254-S at a high dose (20 mg/kg i.v.) or cisplatin at 5 mg/kg (i.v.) also decreased these indices in the slices, and affected urea and creatinine in blood plasma. These results suggested that use of the renal slice technique gives data useful for the evaluation of the nephrotoxicity of 254-S, and that PAH accumulation and the potassium concentration in slices from rats treated with 254-S are indicators of nephrotoxic damage.

Nephrotoxicity of a novel antineoplastic platinum complex, nedaplatin: a comparative study with cisplatin in rats

The present study was designed to characterize the nephrotoxicity induced by the antineoplastic platinum complex nedaplatin (NDP) in rats of different ages in comparison with cisplatin (CDDP). A single dose of 15 mg/kg NDP or 7.5 mg/kg CDDP was administered intravenously to 8-, 11-, or 15-week-old male and female SD rats, which were then sacrificed after ten days. Body weight decreases were observed for both drugs, in direct relation to age. CDDP treatment markedly increased urinary excretion of NAG, γ-GTP, LDH and protein, with peaks on day 4 and complete or partial recovery on day 7; NDP increased NAG, LDH and protein excretion, but to a lesser extent, and these elevations were generally more marked for females. CDDP increased plasma creatinine and BUN in males and females of all age groups at necropsy. No apparent changes were seen following NDP treatment except in the 15-week-old rats. These results also show that NDP is less nephrotoxic than CDDP. CDDP-treated rats showed remarkable proximal tubular lesions in the renal cortex and corticomedullary region, and the papillary lesions were minor. On the other hand, the NDP-induced nephrotoxicity was morphologically characterized by hyaline droplet changes (electron microscopically, hyperplasia of lysosomes), necrosis or hyperplasia of the collecting duct epithelium in the renal papilla and the epithelium covering the papilla. Cortical lesions, indicated by slight tubular dilatation, were found only in the animals with papillary lesions. In summary, NDP is a promising second-generation platinum complex with reduced nephrotoxicity.

Effects of Lisinopril on the Structure of Renal Arterioles

We investigated the effect of long-term administration of the angiotensin-converting enzyme inhibitor lisinopril on renal arterioles in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using a morphometric method and vascular cast technique. Rats were treated with lisinopril beginning at 4 weeks of age. At 15 weeks of age, the kidney vessels were fixed when maximally relaxed. Resin was perfused into the right kidney to make a cast of the renal vasculature. The opposite kidney was used for the morphometric study to evaluate structural changes of the vascular wall. The vascular cast study demonstrated a significant reduction in the lumen diameter of the afferent but not the efferent arterioles in SHR compared with those in WKY. In lisinopril-treated rats, the afferent arteriolar lumen diameters were significantly larger than those of the respective control groups in both strains. However, treatment did not affect the lumen diameter of efferent arterioles in either strain. The morphometric study revealed that the cross-sectional area of afferent arteriolar media was significantly smaller in SHR than WKY, suggesting that the impaired growth of the afferent arteriolar media was involved in the narrowed afferent arteriolar lumen in SHR. The presence of significantly smaller media-lumen ratio, greater media cross-sectional area, and larger internal as well as external diameters of the afferent arterioles in treated SHR than in untreated rats suggested that lisinopril treatment normalizes the structure of the afferent arterioles in SHR by vascular reverse remodeling and by inducing media growth.

ANTIPROTEINURIC EFFECT OF A THROMBOXANE RECEPTOR ANTAGONIST, S-1452, ON RAT DIABETIC NEPHROPATHY AND MURINE LUPUS NEPHRITIS

To shed light on the role of thromboxane A2 (TXA2) in renal injury, we evaluated the effects of S-1452, a TXA2 receptor antagonist, on rats with streptozotocin (STZ)-induced diabetic nephropathy and murine lupus nephritis. In STZ diabetes rats (n = 6), urinary protein excretion significantly increased from 8 weeks and was about 5 times as much as that in normal rats at 10 weeks after induction of diabetes. In S-1452-treated rats (n = 6), increase in urinary protein was rarely observed and was significantly inhibited at 8 and 10 weeks after induction of diabetes. In (NZB x NZW)F1 mice, no proteinuria was detected in vehicle controls (n = 20) and S-1452-treated mice (n = 20) from 0 to 8 weeks after initiation of S-1452 treatment. Proteinuria was observed in 3, 7 and 8 mice in the control group, and 0, 2 and 5 mice in the S-1452 group at 12, 16 and 20 weeks after initiation of S-1452 treatment, respectively. Proteinuria developed more slowly in S-1452-treated mice than in vehicle controls. In conclusion, TXA2 receptor antagonist, S-1452, suppresses the progression of renal injury.

Impaired Urinary Concentrating Ability in Genetically Polyuric Mice

Newly recognized strain of mice with hereditary polyuria (PUS mice) was characterized. Polyuria was inherited as a single autosomal-recessive trait. At 15 weeks, PUS mice excreted hypotonic (urine osmolality: PUS;270.8 ± 15.5 vs. cont.; 3,228.6 ± 163.6 mosm/kg) polyuria (urine volume: PUS; 25.0 ± 1.5 vs. cont.; 1.1 ± 0.1 ml/day). In PUS mice, plasma osmolality was slightly elevated as well as urinary excretion of vasopressin (AVP). Although PUS mice could concentrate urine after 24 h water deprivation, urine osmolality remained low. Blunted response to continuous infusion of dDAVP, a synthetic V2 agonist, was also observed. These in vivo studies indicated renal resistance to AVP contributed to the polyuria in this strain of mice. Microanalysis of isolated tubular segments revealed that AVP-induced cAMP accumulation in cortical collecting ducts (CCD) of PUS mice was significantly lower (60%) with or without a phosphodiesterase inhibitor, IBMX. Vasopressin induced similar cAMP accumulation in medullary ascending limbs of Henle (MAL), and medullary collecting ducts (MCD) between PUS and control mice. In CCDs, PUS mice had low basal adenylate cyclase (AdC) activity and responded less to AVP and forskolin stimulation than control mice. No difference in cyclic AMP phosphodiesterase activity was detected between control and PUS mice. These results indicate that impaired cAMP accumulation due to low AdC activity may be related to the impaired renal concentrating ability observed in this new strain of mice.