Chronic low-dose isotretinoin treatment limits renal damage in subtotally nephrectomized rats.
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.
Morath
Christian
C
Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120, Heidelberg, Germany. christian.morath@med.uni-heidelberg.de
Ratzlaff
Kerstin
K
Dechow
Claudius
C
Schwenger
Vedat
V
Schaier
Matthias
M
Zeier
Benjamin
B
Peters
Jörg
J
Tsukada
Miki
M
Zouboulis
Christos C
CC
Waldherr
Rüdiger
R
Gross
Marie-Luise
ML
Ritz
Eberhard
E
Zeier
Martin
M
Wagner
Jürgen
J
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D024062:Collagen Type V; D003879:Dermatologic Agents; D053773:Transforming Growth Factor beta1; D015474:Isotretinoin
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