Leonid Slobodskoy

Effect of Relaxin in Two Models of Renal Mass Reduction

Background: Relaxin (Rlx), a 6-kD protein hormone, belongs to the insulin growth factor family. We have previously shown that Rlx reduces interstitial fibrosis in a model of chronic papillary necrosis. Hypothesis: The purpose of this study was to extend these observations to a model of renal injury induced by mass reduction. Material and Methods: Renal mass was reduced by either infarction or surgical excision of both poles, with removal of the contralateral kidney. Two weeks later, creatinine clearance was done and animals from both groups implanted with osmotic pumps delivering either Rlx (2 µg/h) or vehicle (Veh). Treatment was continued for 4 weeks. The severity of the glomerular injury was quantified by planimetric measurements. Renal function was assessed by creatinine clearance and plasma creatinine. Results: Rlx significantly decreased systolic blood pressure in animals with infarction. This was accompanied by a decrease in serum creatinine and a slight improvement in creatinine clearance. The severity of the glomerular lesion was reduced by Rlx (sclerosis index, Veh 1.16 ± 0.13 vs. Rlx 0.74 ± 0.16, p = 0.037). In the excision group the animals were normotensive. In this group, Rlx treatment was accompanied by a decrease in serum creatinine (Veh 1.01 ± 0.03 vs. Rlx 0.81 ± 0.05 mg/dl, p = 0.02) and an increase in GFR (Veh 0.90 ± 0.14 vs. Rlx 1.33 ± 0.11 ml/min, p = 0.03). The sclerosis index was also reduced. Conclusion: Rlx decreases renal injury by at least two mechanisms, one by lowering blood pressure as seen in the infarction model, the other independent of blood pressure as seen in the normotensive excision model where there was also a significant functional improvement.

An evaluation of the markers p53 and Ki-67 for their predictive value in prostate cancer

p53 and Ki‐67 are but two markers being evaluated for their predictive value in prostate cancer. The purpose of this study was to compare p53 and Ki‐67 with age, stage, Gleason score, and ploidy for their prognostic abilities in prostate cancer.

Inhibition of PC-3 prostate cancer cell growth in vitro using both antisense oligonucleotides and taxol.

Antisense oligonucleotides (oligos) directed against mRNA-encoding transforming growth factor-α (TGF-α) and the epidermal growth factor receptor (EGFR) have demonstrated in vitro and in vivo efficacy against prostate cancer tumor models. However, many therapeutic agents have increased effectiveness when given in combination with other more established agents. We evaluated the effectiveness of two oligos (3.32 and 6.64 µM/L) known to have significant activity against the PC-3 prostate cell line in combination therapy with the chemotherapeutic agent paclitaxel (Taxol) (2.5 and 5.0 nm). Therapy was evaluated when oligos and Taxol were administered either as (1) single agents, (2) simultaneously in a combined therapy, or (3) sequentially, a form of combination therapy with both agents being administered in a series.We found that when either of the two oligos were given simultaneously with Taxol, no synergistic activity was noted. However, when sequentially administered in a series 1 d apart, a pretreatment with the antisense directed against TGF-α (6.64 µM/L) followed by Taxol (5 nm) had significantly greater activity than these agents similarly administered in the reverse order or simultaneously.

Differential effects of enalapril and irbesartan in experimental papillary necrosis

This study was undertaken to determine whether angiotensin receptor blockers are as renoprotective as angiotensin-converting enzyme inhibitors in an experimental model of chronic interstitial renal disease. Groups of rats received one of the following treatments for 1 week: (1) enalapril, (2) diltiazem, (3) a cocktail of hydralazine, reserpine, and hydrochlorothiazide, or (4) irbesartan (an AT1 antagonist). The animals were injected with bromoethylamine (200 mg/kg), and antihypertensive treatment continued for 1 month. All drugs were effective in lowering the mean arterial pressure. The bromoethylamine-treated rats developed albuminuria and sustained a 40–50% decrease in creatinine clearance. Enalapril and irbesartan reduced albuminuria, but only enalapril partially prevented the decline in creatinine clearance and lowered the number of ED-1-positive cells. Diltiazem and cocktail had no effect on proteinuria, creatinine clearance, or ED-1 cells. In this experimental model, the effects of enalapril and irbesartan were not identical. Both drugs reduced proteinuria, but enalapril was more effective in protecting the renal function. The fact that the AT1 antagonist protected against albuminuria but did not affect the clearance of creatinine implies that the results seen with angiotensin-converting enzyme inhibition may be in part due to an effect on angiotensin II via AT2 receptor blockade or through an effect on bradykinin.

Relaxin decreases renal interstitial fibrosis: A novel treatment to slow the progression of kidney disease?

Interstitial fibrosis is a characteristic finding in numerous pathologies. In the kidney this condition is manifested by a disturbance in tubular architecture such that there is tubular atrophy accompanied by tubular dilation. The normally sparse intercellular space is expanded and filled with extracellular matrix composed mainly of collagen and fibronectin as well as mononuclear cells. If left untreated this may progress to encompass the glomeruli and renal insufficiency may result.