Baseline clinical characteristics.

<p>Baseline clinical characteristics.</p

Epidermal Growth Factor Receptor Inhibition with Erlotinib Partially Prevents Cisplatin-Induced Nephrotoxicity in Rats

<div><p>The effects of blocking the epidermal growth factor receptor (EGFR) in acute kidney injury (AKI) are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP)-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP- nephrotoxicity (CP-N). In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. <i>In vitro</i>, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy.</p></div

Immunohistochemistry for PCNA, ED1, TUNEL, and caspase-3 in the study groups.

<p>Representative pictures stained for (a–c) PCNA, (d–f) ED1, (g–i) TUNEL, and (j–l) caspase-3 in a NC rat (a, d, g, j), a CP+V rat (b, e, h, k), and a CP+E rat (c, f, i, l). Original magnifications: x 400.</p

The prevalence of anti-PLA2R Abs evaluated by ELISA and CIIFA in MN patients.

<p>The prevalence of anti-PLA2R Abs evaluated by ELISA and CIIFA in MN patients.</p

Comparison of the prevalence of serum anti-PLA2R Abs with glomerular PLA2R Ag expression in IMN patients.

<p>Comparison of the prevalence of serum anti-PLA2R Abs with glomerular PLA2R Ag expression in IMN patients.</p

Histopathological characteristics of the anti-PLA2R Ab-positive and -negative IMN patients.

<p>Histopathological characteristics of the anti-PLA2R Ab-positive and -negative IMN patients.</p

Effects of erlotinib on pro-apoptotic and anti-apoptotic protein in the study groups.

<p>Representative western blot analysis for Bax, Bcl-2 and GAPDH (a). Densitometric analysis of western blot for Bax (b), Bcl-2 (c), and Bax/Bcl2 ratio (d) was performed using an image analyzer in each group. Data are expressed as mean ± SEM (n = 5, 14, and 14 for the NC rats, the CP+V rats, and the CP+E rats, respectively). The values were expressed after normalization to GAPDH expression and depicted as the percentage change from the average of normal controls. Mann-Whitney test: *P<0.01, **P<0.01 vs. NC, #P<0.05 vs. CP+V.</p

Clinical characteristics of the anti-PLA2R Ab-positive and -negative IMN patients.

<p>Clinical characteristics of the anti-PLA2R Ab-positive and -negative IMN patients.</p

Schematic representation of experimental protocol.

<p>Cisplatin (CP) nephrotoxicity was induced in 6-week-old male Sprague-Dawley (SD) rats by intraperitoneal injection of CP on day 0. Groups of animals were administered either erlotinib (CP+E) or vehicle (an equivalent volume of saline) (CP+V) daily by oral gavage from day -1 to day 3. An additional five male SD rats were used as normal controls (NC). At 4 days after CP injection, all rats were sacrificed.</p

Effects of erlotinib on gene expression levels for fibrogenic molecules, proinflammatory cytokines, apoptosis-regulatory molecules, and EGFR ligands in the study groups.

<p>Real-time RT-PCR for genes encoding fibrogenic molecules (a), proinflammatory cytokines (b), apoptosis-regulatory molecules (c), and EGFR ligands including proHB-EGF and TGF-α (d) in each group. The horizontal dotted lines show the expression levels of the NC rats. Data are expressed as mean ± SEM (n = 5, 14, and 14 for the NC rats, the CP+V rats, and the CP+E rats, respectively). The values were normalized to the GAPDH transcript levels and then expressed as relative quantification. Mann–Whitney test: *P<0.05, **P<0.01, NS, not significant vs. CP+V.</p