title: Chronic low-dose isotretinoin treatment limits renal damage in subtotally nephrectomized rats.
abstract: Retinoids are anti-proliferative and anti-inflammatory compounds. We had previously shown that retinoids alleviate kidney damage in acute models of renal disease. We now examined whether retinoids are also effective in a chronic renal ablation model. Subtotally nephrectomized rats (SNx; two-third ablation) were compared to sham-operated controls (sham). SNx rats were administered either 10 mg/kg b.w. (low dose, LD) or 40 mg/kg b.w. (high dose, HD) isotretinoin or vehicle (n = 10 per group). The experiment was terminated after 16 weeks. Systolic blood pressure was significantly higher after SNx compared to sham but lower in SNx with LD isotretinoin (vs. SNx + vehicle). Compared to SNx + vehicle, SNx + LD isotretinoin had lower glomerular cell numbers, less glomerular hypertrophy and sclerosis, and less interstitial expansion. Morphological improvement in SNx + LD isotretinoin was accompanied by improvement in creatinine clearance and reduced urinary albumin excretion. In contrast, HD isotretinoin caused aggravation of renal damage with fibrinoid necroses of vessels and elevated urinary albumin excretion despite lower blood pressure. The dichotomous effects of isotretinoin are at least in part due to time- and dose-dependent alterations of transforming growth factor beta1 and collagen IV gene expression as also suggested by cell-culture studies in vascular smooth muscle cells. In addition, isotretinoin affected the systemic and the renal renin-angiotensin system (which was further analyzed in a model of angiotensin II infusion of the rat). Isotretinoin failed to cumulate at LD but cumulated at HD in SNx. We conclude that LD isotretinoin attenuates progressive renal damage, whereas HD isotretinoin cumulates and aggravates renal damage independent of blood pressure reduction.
authors.affiliation: Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120, Heidelberg, Germany. christian.morath@med.uni-heidelberg.de
authors.forename: Christian
authors.initials: C
authors.lastname: Morath
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ratzlaff
authors.forename: Claudius
authors.initials: C
authors.lastname: Dechow
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.forename: Matthias
authors.initials: M
authors.lastname: Schaier
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zeier
authors.forename: Jörg
authors.initials: J
authors.lastname: Peters
authors.forename: Miki
authors.initials: M
authors.lastname: Tsukada
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Waldherr
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Gross
authors.forename: Eberhard
authors.initials: E
authors.lastname: Ritz
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wagner
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D024062:Collagen Type V / Q000096:biosynthesis; D003879:Dermatologic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D015474:Isotretinoin / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D024062:Collagen Type V; D003879:Dermatologic Agents; D053773:Transforming Growth Factor beta1; D015474:Isotretinoin
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