Hedgehog signaling indirectly affects tubular cell survival after obstructive kidney injury.
Hedgehog (Hh) is an evolutionary conserved signaling pathway that has important functions in kidney morphogenesis and adult organ maintenance. Recent work has shown that Hh signaling is reactivated in the kidney after injury and is an important mediator of progressive fibrosis. Pericytes and fibroblasts have been proposed to be the principal cells that respond to Hh ligands, and pharmacological attenuation of Hh signaling has been considered as a possible treatment for fibrosis, but the effect of Hh inhibition on tubular epithelial cells after kidney injury has not been reported. Using genetically modified mice in which tubule-derived hedgehog signaling is increased and mice in which this pathway is conditionally suppressed in pericytes that express the proteoglycan neuron glial protein 2 (NG2), we found that suppression of Hh signaling is associated with decreased macrophage infiltration and tubular proliferation but also increased tubular apoptosis, an effect that correlated with the reduction of tubular β-catenin activity. Collectively, our data suggest a complex function of hedgehog signaling after kidney injury in initiating both reparative and proproliferative, prosurvival processes.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas;
Alysha A
AA
Rauhauser
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas;
Chongyu
C
Ren
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas;
Dongmei
D
Lu
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas;
Binghua
B
Li
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas; Department of Nephrology, Wuhan University, Hubei, Wuhan, China;
Jili
J
Zhu
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas;
Kayla
K
McEnery
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas;
Komal
K
Vadnagara
Department of Pediatrics, University of Iowa, Iowa City, Iowa;
Diana
D
Zepeda-Orozco
Renal Path Diagnostics, Pathologist BioMedical Laboratories and Department of Pathology, Baylor University Medical Center, Dallas, Texas;
Xin J
XJ
Zhou
Department of Pediatrics, Pathology, and Cell Biology, Columbia University, New York, New York;
Fangming
F
Lin
Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and.
Anton M
AM
Jetten
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas Texas; Eugene McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas massimo.attanasio@utsouthwestern.edu.
Massimo
M
Attanasio
D058186:Acute Kidney Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000941:Antigens / Q000378:metabolism; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D014517:Ureteral Obstruction / Q000150:complications*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; D000099216:Chondroitin Sulfate Proteoglycan 4; C495267:CTNNB1 protein, mouse; C498520:Gli1 protein, mouse; C430270:Gli5 protein, mouse; C465570:Shh protein, mouse; C491022:Smo protein, mouse; C514061:ihh protein, mouse; C000541:cyclopamine
UUO; hedgehog signaling; kidney injury