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Jo YI, Cheng H, Wang S, Moeckel GW, Harris RC.
Puromycin induces reversible proteinuric injury in transgenic mice expressing
cyclooxygenase-2 in podocytes.
Nephron Exp Nephrol. 2007;107(3):e87-94.
Division of Nephrology, George M. O'Brien Kidney and Urologic Diseases Center,
Vanderbilt University School of Medicine and Nashville Veterans Affairs
Hospital, Nashville, Tenn 37232, USA.
Previous studies from our own group and others have demonstrated that
cyclooxygenase-2 (COX-2) inhibitors could reduce proteinuria in some
experimental models of progressive renal disease. To investigate a possible role
of COX-2 in podocytes during the course of self-limited glomerular injury, we
administered puromycin nucleoside (PAN) on day 1 (15 mg/100 g BW) and day 3 (30
mg/100 g BW) to wild-type and transgenic mice with podocyte-specific COX-2
expression driven by a nephrin promoter. An additional group received both PAN
and the COX-2-specific inhibitor, SC58236 (6 mg/l in drinking water). There was
no significant difference in the albumin (microg)/creatinine (mg) ratio between
wild-type (26.3 +/- 4.2, n = 8) and transgenic (28.9 +/- 2.3, n = 8) mice under
baseline conditions. PAN induced significant albuminuria only in the transgenic
mice with a peak at day 3: 72.1 +/- 8.9 microg/mg creatinine (n = 12, p < 0.05,
compared with basal level), which remitted by day 10 (37.4 +/- 4.4 microg/mg, n
= 7, p < 0.05, compared with day 3). Electron microscopy demonstrated that PAN
caused 56.7 +/- 4.2% foot process effacement in transgenic mice compared with
38.8 +/- 4.1% in wild type at day 3. PAN increased immunoreactive COX-2 in
glomeruli from transgenic mice (day 3: 1.47 +/- 0.08 fold; day 10: 1.25 +/- 0.16
fold, n = 5-9, p < 0.05 compared with basal level), which was restricted to
podocytes. Real time PCR indicated that endogenous COX-2 mRNA increased (2.6 +/-
0.1 fold of wild-type control at day 3 and 2.2 +/- 0.2 at day 10, n = 4, p <
0.05), while the nephrin-driven COX-2 mRNA was unchanged. Nephrin mRNA and
protein expression were decreased by PAN in the transgenic mice. The
COX-2-specific inhibitor, SC58236, reduced foot process effacement in transgenic
mice administered PAN to 21.7 +/- 5.2% and significantly reduced the albuminuria
at day 3 (42.2 +/- 3.8, n = 13, p < 0.05 compared with untreated) without
significantly altering COX-2 expression. In summary, in transgenic mice with
podocyte COX-2 overexpression, PAN increased albuminuria and induced foot
process fusion. Thus, increased COX-2 expression increased podocyte
susceptibility to further injury. Copyright 2007 S. Karger AG, Basel.
PMID: 17890881 |
