Amiloride modifies the progression of lithium-induced renal interstitial fibrosis.
OBJECTIVE
Long-term administration of lithium has been associated with the development of a chronic interstitial fibrosis in addition to nephrogenic diabetes insipidus (NDI). Earlier studies have demonstrated that amiloride, by blocking the epithelial sodium channel ENaC and thus preventing lithium uptake into the principal cells of the collecting ducts, can partially reverse lithium-induced NDI. However, there are no long-term studies examining whether or not amiloride also modifies the progressive chronic interstitial fibrosis and tubular atrophy often evident with long-term lithium exposure.


METHODS
Using an established animal model of lithium-induced chronic interstitial fibrosis, rats were treated with amiloride and lithium for 5 months following 1 month of exposure to lithium alone and compared with control animals and those given only lithium.


CONCLUSIONS
In this study, the 5 months of amiloride therapy partially mitigated the lithium-induced NDI and limited the further progression of lithium-induced kidney fibrosis. This improvement was associated with decreased expression of the pro-fibrotic connective tissue growth factor (CTGF), along with reduced myofibroblast infiltration and decreased collagen deposition around the distended cortical collecting ducts. This may, in part, be mediated by modifying lithium-induced alterations in β-catenin activity through its effects on GSK-3β.
Departments of Medicine, University of Otago, Dunedin, New Zealand.|Departments of Physiology, University of Otago, Dunedin, New Zealand.|Molecular Breast Pathology University of Queensland Centre for Clinical Research (UQCCR) Herston QLD, Australia.
Priyakshi
P
Kalita-De Croft
Departments of Medicine, University of Otago, Dunedin, New Zealand.
Jennifer J
JJ
Bedford
Departments of Medicine, University of Otago, Dunedin, New Zealand.
John P
JP
Leader
Departments of Medicine, University of Otago, Dunedin, New Zealand.
Robert J
RJ
Walker
D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology*; D005355:Fibrosis; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016651:Lithium Carbonate; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C526316:CCN2 protein, rat; D024061:Collagen Type III; C495268:Ctnnb1 protein, rat; D062686:Epithelial Sodium Channel Blockers; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; D016651:Lithium Carbonate; D000584:Amiloride; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat
Lithium; amiloride; chronic interstitial fibrosis