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      Renoprotective Effects of a Selective Estrogen Receptor Modulator, Raloxifene, in an Animal Model of Diabetic Nephropathy

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          Background/Aims: Our previous studies have shown that supplementation with 17β-estradiol (E<sub>2</sub>) from the onset of diabetes attenuates diabetic nephropathy. However, E<sub>2</sub> is accompanied by feminizing effects as well as adverse side effects on other organs. The current study examined the renoprotective effects of a selective estrogen receptor modulator, raloxifene (RAL), in an experimental model of diabetic nephropathy. RAL activates estrogen receptors and estrogen-receptor-mediated cellular events without the side effects of E<sub>2</sub>. Methods: The study was performed in Sprague-Dawley nondiabetic (ND), streptozotocin-induced diabetic (D) and streptozotocin-induced D + RAL rats (n = 6/group). Results: After 12 weeks of treatment, D was associated with increased urine albumin excretion (ND: 4.2 ± 0.4; D: 41.3 ± 9.0 mg/day), glomerulosclerosis [glomerulosclerotic index; ND: 0.26 ± 0.04; D: 1.86 ± 0.80 arbitrary units (AU)], tubulointerstitial fibrosis (tubulointerstitial fibrosis index; ND: 0.37 ± 0.05; D: 2.12 ± 0.50 AU), increased collagen type I [ND: 1.31 ± 0.07; D: 4.65 ± 0.09 relative optical density (ROD)], collagen type IV (ND: 0.64 ± 0.03; D: 1.37 ± 0.11 ROD) and transforming growth factor beta (TGF-β) protein expression (ND: 0.65 ± 0.08; D: 1.25 ± 0.10 ROD), increased density of CD68-positive cells (ND: 1.37 ± 3.02; D: 29.2 ± 1.74 cells/mm<sup>2</sup>) and increased plasma levels of interleukin-6 (ND: 14.8 ± 5.0; D: 51.3 ± 14.0 pg/ml). Treatment with RAL partially or fully attenuated these processes (urine albumin excretion: 21.0 ± 5.0 mg/day; glomerulosclerotic index: 0.40 ± 0.06 AU; tubulointerstitial fibrosis index: 0.20 ± 0.04 AU; collagen type I: 2.55 ± 0.49 ROD; collagen type IV: 0.70 ± 0.09 ROD; TGF-β: 0.91 ± 0.08 ROD; CD68: 6.03 ± 2.38 cells/mm<sup>2</sup>; interleukin-6: 31.2 ± 5.0 pg/ml). Conclusions: Our data indicate that treatment with RAL attenuates albuminuria and renal structural changes associated with diabetes.

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          Most cited references 27

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          Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.

          Proteinuria or albuminuria is an established risk marker for progressive renal function loss. Albuminuria can be effectively lowered with antihypertensive drugs that interrupt the renin-angiotensin system (RAS). We investigated whether albuminuria could not only serve as a marker of renal disease, but also function as a monitor of the renoprotective efficacy of RAS intervention by the angiotensin II (Ang II) antagonist, losartan, in patients with diabetic nephropathy. The data from the RENAAL (Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) study, a double-blind, randomized trial, were used to examine the effects of losartan on the renal outcome [i.e., the primary composite end point of doubling of serum creatinine, end-stage renal disease (ESRD) or death] in 1513 type 2 diabetic patients with nephropathy. We examined the effect of the degree of albuminuria at baseline, initial antiproteinuric response to therapy, and the degree of remaining (residual) albuminuria on renal outcome (either the primary composite end point of RENAAL or ESRD). We also evaluated the contribution to renal protection of the antiproteinuric effect of losartan independently of changes in blood pressure. Baseline albuminuria is almost linearly related to renal outcome, and is the strongest predictor among all measured well-known baseline risk parameters. After adjusting for baseline risk markers of age, gender, race, weight, smoking, sitting diastolic blood pressure, sitting systolic blood pressure, total cholesterol, serum creatinine, albuminuria, hemoglobin, and hemoglobin A(1c) (HbA(1c)) patients with high baseline albuminuria (> or =3.0 g/g creatinine) showed a 5.2-fold (95% CI 4.3-6.3) increased risk for reaching a renal end point, and a 8.1-fold (95% CI 6.1-10.8) increased risk for progressing to ESRD, compared to the low albuminuria group (<1.5 g/g). The changes in albuminuria in the first 6 months of therapy are roughly linearly related to the degree of long-term renal protection: every 50% reduction in albuminuria in the first 6 months was associated with a reduction in risk of 36% for renal end point and 45% for ESRD during later follow-up. Albuminuria at month 6, designated residual albuminuria, showed a linear relationship with renal outcome, almost identical to the relationship between baseline albuminuria and renal risk. Losartan reduced albuminuria by 28% (95% CI -25% to -36%), while placebo increased albuminuria by 4% (95% CI +8% to -1%) in the first 6 months of therapy. The specific (beyond blood pressure lowering) renoprotective effect of the Ang II antagonist, losartan, in this study is for the major part explained by its antialbuminuric effect (approximately 100% for the renal end point, and 50% for ESRD end point). Albuminuria is the predominant renal risk marker in patients with type 2 diabetic nephropathy on conventional treatment; the higher the albuminuria, the greater the renal risk. Reduction in albuminuria is associated with a proportional effect on renal protection, the greater the reduction the greater the renal protection. The residual albuminuria on therapy (month 6) is as strong a marker of renal outcome as is baseline albuminuria. The antiproteinuric effect of losartan explains a major component of its specific renoprotective effect. In conclusion, albuminuria should be considered a risk marker for progressive loss of renal function in type 2 diabetes with nephropathy, as well as a target for therapy. Reduction of residual albuminuria to the lowest achievable level should be viewed as a goal for future renoprotective treatments.
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            Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women.

            Higher levels of endogenous sex steroid hormones are associated with increased risks of breast cancer in postmenopausal women. Data for premenopausal women are sparse, in part because of the complexity of measuring hormone levels that vary cyclically. We prospectively evaluated associations between plasma sex hormone levels and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II. From 1996 to 1999, blood samples were collected from 18,521 premenopausal women during the early follicular and midluteal phases of their menstrual cycles. A total of 197 cases of breast cancer were diagnosed among these women after blood collection and before June 1, 2003; these case subjects were matched to 394 control subjects. Logistic regression models, controlling for breast cancer risk factors, were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Women in the highest (versus the lowest) quartiles of follicular total and free estradiol levels had statistically significantly increased risks of breast cancer (RR = 2.1 [95% CI = 1.1 to 4.1], P(trend) = .08, and RR = 2.4 [95% CI = 1.3 to 4.5], P(trend) = .01, respectively); the associations were stronger for invasive breast cancer and for estrogen and progesterone receptor-positive (ER+/PR+) tumors. Luteal estradiol levels were not associated with breast cancer risk. Higher levels of total and free testosterone and androstenedione in both menstrual cycle phases were associated with modest, non-statistically significant increases in overall risk of breast cancer and with stronger, statistically significant increases in risks of invasive and ER+/PR+ cancers (e.g., RR of invasive cancers for the top [versus bottom] quartile of luteal total testosterone levels = 2.0 [95% CI = 1.1 to 3.6], P(trend) = .05, and RR of ER+/PR+ cancers = 2.9 [95% CI = 1.4 to 6.0], P(trend) = .02). Levels of estrone, estrone sulfate, progesterone, and sex hormone-binding globulin were not associated with breast cancer risk. The absolute number of cases observed over 3 years were 30 among women in the lowest 25% of follicular total estradiol levels and 50 among women in the highest 25%. Levels of circulating estrogens and androgens may be important in the etiology of premenopausal breast cancer.
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              Macrophage accumulation in human progressive diabetic nephropathy.

              Diabetic nephropathy is a major global health problem. Progression to renal failure is common; however, the mechanisms are unknown. Experimental models suggest a role for macrophages. Therefore, macrophage accumulation and its relationship to the subsequent clinical course were studied. A retrospective study of baseline histology and the subsequent clinical course over at least 5 years involving 20 consecutive patients with a histological and clinical diagnosis of diabetic nephropathy was performed. The relationship between macrophage accumulation in renal biopsy tissue (KP-1/anti-CD68+ cells), baseline measures of known predictors of progression (proteinuria, tubulointerstitial damage, myofibroblast accumulation) and progression over 5 years (plot of reciprocal of serum creatinine) was quantified. Accumulation of macrophages was apparent in the glomeruli (2.8 + 0.7/gcs vs 1.0 + 0.2 for normals, P = not significant) and interstitium (296.9 + 63.3/mm(2) vs 19.0 + 1.3/mm(2) for normals, P = 0.002) of patients with diabetic nephropathy. Glomerular macrophage number correlated with baseline serum creatinine (r = 0.548, P = 0.012) but not with progression of renal failure as glomerular macrophages were prevalent in early, but not advanced diabetic nephropathy. Interstitial macrophage accumulation correlated strongly with serum creatinine (r = 0.649, P = 0.002), proteinuria (r = 0.779, P < 0.0001), interstitial fibrosis (r = 0.774, P < 0.0001) and inversely with the slope of 1/serum creatinine (r = -0.531, P = 0.023). Macrophages accumulate within glomeruli and the interstitium in diabetic nephropathy and the intensity of the interstitial infiltrate is proportional to the rate of subsequent decline in renal function. These human data support animal studies that suggest a pathogenic role for the macrophage in diabetic nephropathy.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                April 2007
                15 February 2007
                : 27
                : 2
                : 120-128
                aDepartment of Medicine and bCenter for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, Washington, D.C., USA
                99837 PMC3179626 Am J Nephrol 2007;27:120–128
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 36, Pages: 9
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                Original Report: Laboratory Investigation


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