HIF activation protects from acute kidney injury.
The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1alpha protein in vitro or in vivo under normoxic conditions. However, hypoxic preconditioning of cisplatin-treated proximal tubular cells in culture reduced apoptosis in an HIF-1alpha-dependent fashion and increased cell proliferation as measured by BrdU incorporation. In vivo, rats preconditioned with carbon monoxide before cisplatin administration had significantly better renal function than rats kept in normoxic conditions throughout. Moreover, the histomorphological extent of renal damage and tubular apoptosis was reduced by the preconditional treatment. Therefore, development of pharmacologic agents to induce renal HIF might provide a new approach to ameliorate cisplatin-induced nephrotoxicity.
Weidemann
Alexander
A
Medical Clinic 4, Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen Nuremberg, Krankenhausstrasse 12, D - 91054 Erlangen, Germany.
Bernhardt
Wanja M
WM
Klanke
Bernd
B
Daniel
Christoph
C
Buchholz
Björn
B
Câmpean
Valentina
V
Amann
Kerstin
K
Warnecke
Christina
C
Wiesener
Michael S
MS
Eckardt
Kai-Uwe
KU
Willam
Carsten
C
D058186:Acute Kidney Injury / Q000139:chemically induced; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D004247:DNA / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002248:Carbon Monoxide; D004247:DNA; D002945:Cisplatin