T-type calcium channel blockade as a therapeutic strategy against renal injury in rats with subtotal nephrectomy.
T-type calcium channel blockers have been previously shown to protect glomeruli from hypertension by regulating renal arteriolar tone. To examine whether blockade of these channels has a role in protection against tubulointerstitial damage, we used a stereo-selective T-type calcium channel blocker R(-)-efonidipine and studied its effect on the progression of this type of renal injury in spontaneously hypertensive rats that had undergone subtotal nephrectomy. Treatment with racemic efonidipine for 7 weeks significantly reduced systolic blood pressure and proteinuria. The R(-)-enantiomer, however, had no effect on blood pressure but significantly reduced proteinuria compared to vehicle-treated rats. Both agents blunted the increase in tubulointerstitial fibrosis, renal expression of alpha-smooth muscle actin and vimentin along with transforming growth factor-beta (TGF-beta)-induced renal Rho-kinase activity seen in the control group. Subtotal nephrectomy enhanced renal T-type calcium channel alpha1G subunit expression mimicked in angiotensin II-stimulated mesangial cells or TGF-beta-stimulated proximal tubular cells. Our study shows that T-type calcium channel blockade has renal protective actions that depend not only on hemodynamic effects but also pertain to Rho-kinase activity, tubulointerstitial fibrosis, and epithelial-mesenchymal transitions.
Sugano
N
N
Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
Wakino
S
S
Kanda
T
T
Tatematsu
S
S
Homma
K
K
Yoshioka
K
K
Hasegawa
K
K
Hara
Y
Y
Suetsugu
Y
Y
Yoshizawa
T
T
Hara
Y
Y
Utsunomiya
Y
Y
Tokudome
G
G
Hosoya
T
T
Saruta
T
T
Hayashi
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002908:Chronic Disease; D004095:Dihydropyridines / Q000627:therapeutic use*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D009392:Nephrectomy / Q000379:methods; D009596:Nitrophenols / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; C066425:efonidipine