Combination Therapy with Telmisartan and Oxacalcitriol Suppresses the Progression of Murine Adriamycin Nephropathy

• Published in: Nephron Vol. 129; no. 2; pp. 143 - 154
• Main Authors: Jeong, Kyung Hwan, Asanuma, Katsuhiko, Lydia, Aida, Takagi, Miyuki, Asao, Rin, Kodama, Fumiko, Asanuma, Etsuko, Tomino, Yasuhiko
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2015
• Subjects: Albuminuria - drug therapy; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Antibiotics, Antineoplastic; Apoptosis - drug effects; Benzimidazoles - therapeutic use; Benzoates - therapeutic use; Calcitriol - analogs & derivatives; Calcitriol - therapeutic use; Doxorubicin; Drug Therapy, Combination; Experimental Nephrology: Original Paper; Female; Glomerulosclerosis, Focal Segmental - drug therapy; Intracellular Signaling Peptides and Proteins - metabolism; Kidney Diseases - chemically induced; Kidney Diseases - drug therapy; Kidney Diseases - pathology; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Podocytes - pathology; Vitamin D analog; Podocyte; AT1 receptor antagonist; Adriamycin nephropathy
• ISSN: 1660-8151; 2235-3186
• DOI: 10.1159/000369346

Background: Blockade of the renin-angiotensin system plays a key role in suppressing the progression of renal diseases. It has not been well established whether this therapy provides additional effects when combined with vitamin D or its analog in a model of adriamycin (ADR)-induced nephropathy. Methods: We evaluated the effect of an angiotensin II subtype 1 receptor blocker (telmisartan) combined with a vitamin D analog (oxacalcitriol) on mice ADR-induced nephropathy (9.5 mg/kg single intravenous injection). We also tested immortalized murine podocytes to examine the effects on podocyte apoptosis. Results: Mice with ADR-induced nephropathy developed progressive albuminuria and glomerulosclerosis within 30 days accompanied by decreased expression of slit diaphragm (SD)-associated proteins (nephrin and podocin), reduced numbers of podocytes, and increased systolic blood pressure. Treatment with telmisartan or oxacalcitriol alone moderately ameliorated kidney injury. The combined treatment most effectively reduced the albuminuria and glomerulosclerosis. These effects were accompanied by the restoration of SD-associated proteins, reduction of podocyte apoptosis, and prevention of podocyte depletion in the glomeruli. Treatment with telmisartan, oxacalcitriol, and the combination therapy resulted in similar reductions in systolic blood pressure. In cultured murine podocytes, ADR stimulated the expression of Bax/Bcl-2 and apoptosis as determined by Hoechst 33342 staining. These changes were effectively inhibited by telmisartan or oxacalcitriol, but the combination treatment most effectively reduced these effects. Conclusions: These data demonstrated that application of a renin-angiotensin system blocker plus a vitamin D analog effectively prevented renal injury in ADR-induced nephropathy. The observed amelioration of renal injury may be partly attributable to antiapoptotic effects in podocytes.