Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker

Figures

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  Figure 1. Long-term ARB and TRX treatment had different effects on renal function. (A) Changes in blood pressure (BP) from biopsy to autopsy. Each point represents the change in BP from biopsy (Bx) to autopsy (Ax) in an individual rat. The rate of BP increase was less in ARB and TRX compared to Control. (B) Changes in proteinuria from biopsy to autopsy. TRX had more proteinuria than ARB. (C) GFR decreased more from biopsy to autopsy in TRX compared to Control and ARB. (D) Changes in urine Kim-1 from biopsy to autopsy (normalized by urine creatinine, Cr). The change of urine Kim-1 in TRX was less than in ARB vs. Control (p < 0.05).

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  Figure 2. Long-term ARB and TRX reduced glomerulosclerosis but not interstitial fibrosis. (A,B) Changes in sclerosis index (SI, 0-4 scale) from biopsy to autopsy. SI increased in untreated control 5/6 Nx rats from biopsy to autopsy, with less increase in ARB and TRX. (C,D). Changes in interstitial fibrosis (Sirius red) from biopsy to autopsy were similar among groups (p > 0.05).

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  Figure 3. Long-term ARB, but not TRX, maintained glomerular WT-1+ cell density, with possible PEC-podocyte transition. (A) Immunofluorescence staining for WT-1 (green), representing mature podocytes (arrows, positive cells, blue nucleus, X400). ARB resulted in more preserved glomerular WT-1 positive cell density (p < 0.05 vs. Control and TRX). (B) Double immunofluorescence staining for CD44 and synaptopodin. CD44 is a marker of activated PECs (green), and synaptopodin stains podocytes (red) (arrows, double-positive cells, blue nucleus, ×400). ARB increased double-positive cells on the glomerular tuft (p < 0.05 vs. Control and TRX).

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  Figure 4. Long-term ARB and TRX treatment and cardiovascular parameters. (A) ARB numerically reduced myocyte hypertrophy and heart fibrosis compared to the control group. (B) ARB ameliorated the increase in plasma aldosterone level compared to Control (p < 0.05). (C) Infiltrating macrophages were reduced by ARB but not by TRX treatment, vs. Control (×200).

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  Figure 5. Long-term ARB, but not TRX, increased survival in the rat 5/6 Nx model. (A) Kaplan–Meier curves of survival time, and treatment effects. More rats survived with ARB compared to TRX or Control (Log-rank test: Control vs. ARB, p < 0.01; TRX vs. ARB, p < 0.05; Control vs. TRX, p = 0.5). (B) Hazard ratios in Cox proportional hazards model. The ARB treatment hazard ratio is 0.26, whereas in untreated Control rats, the hazard ratio related to biopsy glomerular sclerosis severity is 4.86. (C) The benefit on survival associated with ARB treatment was independent of starting sclerosis level. The effect of SI on survival was based on a Cox regression model, and effect of SI and its interaction with the treatment groups modeled as described in methods.