Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats.
BACKGROUND
Although Rho-kinase is reported to play an important role in vascular injury, the contribution of Rho-kinase to the progression of renal injury remains unestablished.


METHODS
We examined the effect of fasudil, a Rho-kinase inhibitor, on the progression of renal injury in subtotally nephrectomized spontaneously hypertensive rats (SHR). Rats were randomly assigned to three groups: sham-operated SHR; salt-loaded subtotally nephrectomized rats (SHR-subtotal nephrectomy); SHR-subtotal nephrectomy given fasudil for 6 weeks (SHR-subtotal nephrectomy + fasudil; 3 mg/kg/day). Renal morphologic and molecular analysis as well as urinary protein excretion was evaluated.


RESULTS
In SHR-subtotal nephrectomy treated with fasudil, systolic blood pressure was not significantly different from that in SHR-subtotal nephrectomy without fasudil (208 +/- 8 mm Hg vs. 217 +/- 14 mm Hg). Urinary protein excretion was markedly increased in SHR-subtotal nephrectomy (124 +/- 16 mg/day), but this increase was significantly suppressed by fasudil (79 +/- 12 mg/day). Renal histologic examination revealed that fasudil improved glomerular and tubulointerstitial injury scores with parallel amelioration of proliferating cell nuclear antigen-positive and ED-1-positive cell infiltration. Furthermore, Western blot analyses showed that both expression and activity of Rho-kinase were enhanced in SHR-subtotal nephrectomy, compared with those in SHR without nephrectomy, and fasudil suppressed Rho-kinase activity. Finally, fasudil up-regulated the expression of p27kip1, a cyclin-dependent kinase inhibitor, and increased the p27kip1 immunopositive cells in both glomeruli and tubulointerstitium with the use of immunohistochemistry.


CONCLUSIONS
Rho-kinase pathway is involved in the pathogenesis of renal injury. Furthermore, the inhibition of Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury in part through the p27kip1 up-regulation and the subsequent inhibition of cell proliferation and macrophage recruitment.
Kanda
Takeshi
T
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Wakino
Shu
S
Hayashi
Koichi
K
Homma
Koichiro
K
Ozawa
Yuri
Y
Saruta
Takao
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D053331:Ectodysplasins; D006973:Hypertension / Q000150:complications*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009392:Nephrectomy / Q000379:methods*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011918:Rats, Inbred SHR; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D053331:Ectodysplasins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C049347:fasudil