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. 2011 Oct;22(10):1863-75.
doi: 10.1681/ASN.2010111196. Epub 2011 Aug 25.

Valproic acid attenuates proteinuria and kidney injury

Katrien Van Beneden  1 , Caroline Geers, Marina Pauwels, Inge Mannaerts, Dierik Verbeelen, Leo A van Grunsven, Christiane Van den Branden
Affiliations

Valproic acid attenuates proteinuria and kidney injury

Katrien Van Beneden et al. J Am Soc Nephrol. 2011 Oct.

Abstract

Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD.

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Figures

Figure 1.
Figure 1.
Valproic acid prevents proteinuria and kidney injury in adriamycin nephropathy. (A) Schematic of the experimental design for pre-VPA treatment. (B) Proteinuria expressed as total urinary protein over creatinine is prevented when VPA treatment was started 3 days prior (pre-VPA, n = 5) to ADR injection. (C) In the ADR group (n = 9) serum cholesterol (mg/dl) is elevated significantly versus controls (n = 5) and versus the pre-VPA group. (D) Blinded quantitative histologic evaluation of glomerulosclerosis was scored by a pathologist. (E) Representative cortical fields demonstrate kidney injury at the end of the experiment in the different groups of mice as indicated. Kidney sections were subjected to PAS staining. (#P < 0.001; **P < 0.01; *P < 0.05)
Figure 2.
Figure 2.
Valproic acid corrects an established proteinuria and limits kidney injury in adriamycin nephropathy. (A) Schematic of the experimental design for post-VPA treatment. (B) Proteinuria expressed as total urinary protein over creatinine was detected during the course of the experiment until 23 days after ADR injection. When VPA treatment was postponed 10 days after ADR injection (post-VPA group, n = 14), proteinuria drops already 3 days after the start of the treatment and stays significantly lower compared with the ADR group (n = 9). (C) Hypercholesterolemia (mg/dl) is observed in the ADR-10d group (n = 6), in the ADR group at the end of the experiment, and in the post-VPA group. (D) Blinded quantitative histologic evaluation of glomerulosclerotic lesions were scored by a pathologist. (E) Representative cortical fields demonstrate kidney injury in the different groups of mice as indicated (PAS staining). Note: In glomeruli of post-VPA–treated animals, a clear swelling of the glomerulus with mesangial expansion (asterisk) is found comparable with the ADR-10d group. This glomerulosclerotic stage precedes the one seen in the ADR group at the end of the experiment, where glomeruli collapse and are surrounded by a fibrotic Bowman's capsule. (#P < 0.001; **P < 0.01; *P < 0.05)
Figure 3.
Figure 3.
Valproic acid increases glomerular acetylation. (A) Representative cortical fields are shown for the acetyl-H3K9 staining (dotted circle surrounds a glomerulus). (B) Glomerular acetylation in 20 glomeruli of at least three animals of each group was quantified by using ImageJ software. (#P < 0.001; **P < 0.01; *P < 0.05)
Figure 4.
Figure 4.
Valproic acid hampers renal fibrosis. (A through D) Graphic presentation shows the relative renal mRNA levels of α-SMA, TIMP-1, collagen type-1α1, and TGF-β1 determined by qPCR in the different groups. (E) Picrosirius Red staining was performed to visualize the collagen deposition in all groups. (F) ImageJ software was used for the quantification of the Picrosirius Red area. (G) Tubulointerstitial fibrosis score was assessed by a pathologist on Masson trichrome-stained sections. (#P < 0.001; **P < 0.01; *P < 0.05)
Figure 5.
Figure 5.
Valproic acid hampers renal inflammation. (A through D) Graphic presentation shows the relative renal mRNA levels of MCP-1, MIP-1β, TNF-α, and VCAM-1 determined by qPCR in the different groups. (E) Representative cortical fields show the interstitial macrophage infiltration of ER-HR3+ macrophages/monocytes (arrows) for all groups. (F) ER-HR3+ cells were counted in 100 cortical fields for each animal to quantify the degree of inflammation. (#P < 0.001; **P < 0.01; *P < 0.05)
Figure 6.
Figure 6.
Valproic acid reduces glomerular injury in adriamycin nephropathy. (A) To quantify the rate of apoptosis in the glomeruli, a TUNEL staining was done and positive cells in 100 glomeruli of at least three animals of each group were counted. (B) Proliferation was quantified by counting the Ki67+ cells in 100 glomeruli of at least three animals of each group. (**P < 0.01; *P < 0.05)
Figure 7.
Figure 7.
Valproic acid reduces podocyte detachment and injury in adriamycin nephropathy. (A) Transmission electron microscopy was performed to study the ultrastructure of the glomeruli. Podocytes of ADR animals revealed complete effacement of the epithelial foot processes (arrows), vacuolization (arrowhead), and amorphous electron-dense material (asterisk). Original magnification, ×6200. (B) Urinary podocin mRNA was detected at key time points in the post-VPA treatment setup by qPCR. At day 10 the urinary podocin mRNA level reaches a peak, coinciding with the proteinuria peak. After 3 days of VPA treatment the urinary podocin mRNA level has already dropped significantly compared with that of the ADR group. (#P < 0.001; **P < 0.01)
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