title: PKC-delta promotes renal tubular cell apoptosis associated with proteinuria.
abstract: Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time- and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-delta early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-delta, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-delta blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-delta in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-delta-knockout mice. Taken together, these results suggest that activation of PKC-delta promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans' Affairs Medical Center, Augusta, Georgia 30912, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Li
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.forename: Guie
authors.initials: G
authors.lastname: Dong
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000418:Albumins / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013311:Streptozocin; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000418:Albumins; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013311:Streptozocin; D045304:Cytochromes c; C085746:rottlerin; D051745:Protein Kinase C-delta; D020169:Caspases
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