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1 Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, United States
2 Medicine-Renal, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
3 Pathology, Instituto Nacional de Ciencias Medicas y Nutricion, SZ, Mexico City, Mexico
4 Harvard Institutes of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
5 , Instituto de Investigaciones Biomedicas, UNAM, Mexico; Dept de Nefrologia y Metabolismo Mineral, Inst Nacional de la Nutrition Salvador Zubiran, Vasco de Quiroga No. 15, Mexico, D.F., Mexico
6 , Instituto de Investigaciones Biomedicas, UNAM, Mexico
* To whom correspondence should be addressed. E-mail: nab{at}biomedicas.unam.mx.
Recent studies from our laboratory have shown that the mineralocorticoid receptor blockade with spironolactone (Sp) prevented renal dysfunction and reduced renal injury in both acute and chronic cyclosporine (CsA) nephrotoxicity. This study was design to evaluate if Sp administration reduces functional and structural renal damage associated with existing chronic CsA nephrotoxicity.
Twenty eight male Wistar rats were fed a low sodium diet. Fourteen received vehicle (V) and the others were treated with CsA (15mg/K sc). After 18 days one half of each group received Sp (20 mg/K p.o.) for the subsequent 18 days. Creatinine clearance, arteriolopathy, tubulo-interstitial fibrosis, arteriolar thickening, glomerular diameter, apoptosis index and TGF-
, procaspase-3 and kidney injury molecule 1 (Kim-1) mRNA levels, as well as Kim-1 shedding in urine were evaluated.
Spironolactone reduced the progression of renal dysfunction and tubulo-interstitial fibrosis in preexisting chronic CsA nephrotoxicity. There was a significant reduction of arteriolar thickening in the CsA+Sp group that was associated with greater glomerular diameter and reduction of apoptosis index. These renoprotective effects were associated with reduction of TGF-, procaspase-3 and Kim-1 mRNA levels as well as Kim-1 shedding into the urine.
In conclusion mineralocorticoid receptor (MR) blockade with spironolactone prevented the progression of renal injury in preexisting chronic CsA nephropathy. These results suggest that spironolactone may reduce CsA-induced established nephrotoxicity in patients.
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