Mycophenolate mofetil prevents arteriolopathy and renal injury in subtotal ablation despite persistent hypertension.
BACKGROUND
Although renal protective effect of interrupting the inflammatory process is well established, it is still controversial if it also prevents the glomerular hemodynamic disturbances that initiate renal injury. We investigated the effects of suppressing inflammation with mycophenolate mofetil (MMF) on glomerular hemodynamics, arteriolar structural changes, and renal histologic injury in rats with subtotal renal ablation


METHODS
Micropuncture studies were performed 30 days after 5/6 nephrectomy in rats untreated and treated with MMF (30 mg/kg/day). Renal histology, immunohistochemistry for lymphocytes, macrophages and inducible nitric oxide synthase (iNOS) expression, as well as afferent arteriolar (AA) morphometry was evaluated.


RESULTS
Renal ablation significantly increased proteinuria (6.8 to 82.7 mg/day), mean arterial pressure (MAP) (120 to 166 mm Hg), single-nephron glomerular filtration rate (SNGFR) (34.8 to 56.3 nL/min), glomerular plasma flow (QA) (117.7 to 246.9 nL/min), and glomerular capillary pressure (PGC) (48.9 to 61.0 mm Hg). Afferent resistance (AR), efferent resistance, and ultrafiltration coefficient remained unchanged. Despite persisting arterial hypertension (152 mm Hg), MMF prevented proteinuria (13.3 mg/day), and significantly reduced SNGFR (44.4 nL/min), PGC (49.1 mm Hg), and QA (163.2 nL/min) due to a rise in AR (3.13 vs. 2.18 1010 dyn/sec/cm-5). Glomerular sclerosis, tubulointerstitial damage, lymphocyte and macrophage infiltration, and iNOS expression were significantly reduced by MMF, in addition hypertrophy of AA resistance evaluated by the media/lumen ratio was prevented (P < 0.001).


CONCLUSIONS
Reduction in proteinuria, SNGFR, QA, and PGC, despite elevated MAP, indicate preservation of AA function. These results suggest that inflammation associated arteriolopathy of AA contributes to glomerular hemodynamic disturbances that participate in the progression of renal disease.
Tapia
Edilia
E
Departments of Nephrology and Pathology, Instituto Nacional de Cardiología "Ignacio Chávez," México City, México. ediliatapia@hotmail.com
Franco
Martha
M
Sánchez-Lozada
Laura G
LG
Soto
Virgilia
V
Avila-Casado
Carmen
C
Santamaría
José
J
Quiroz
Yasmir
Y
Rodríguez-Iturbe
Bernardo
B
Herrera-Acosta
Jaime
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001160:Arterioles / Q000473:pathology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000473:pathology; D007668:Kidney / Q000098:blood supply; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009392:Nephrectomy; D009393:Nephritis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D011507:Proteinuria / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009173:Mycophenolic Acid