PKC-δ 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-␦ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-␦, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-␦ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-␦ 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-␦-knockout mice. Taken together, these results suggest that activation of PKC-␦ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.

(Na+ + K+)-ATPase Is a Target for Phosphoinositide 3-Kinase/Protein Kinase B and Protein Kinase C Pathways Triggered by Albumin

“…Lee and Han (24) showed that a higher albumin concentration (3-20 mg/ml) activates Ca 2ϩ -dependent PKC, which phosphorylates the epidermal growth factor receptor in primary rabbit PT cells leading to cell growth. However, Li et al (30) showed that albumin (10 -40 mg/ml) activates PKC␦, promoting tubular cell injury and death during albuminuria in a rat proximal tubular cell line. Here, we observed that a higher albumin concentration (10 -20 mg/ml) did not change PKC activity compared with controls in the absence of albumin.…”

Mitochondrial dysfunction in the pathophysiology of renal diseases

“…However, excessive proteinuria brings abundant FFAs into tubular mitochondria, thus accelerating ROS production (105). In proximal tubular cells, albumin activates PKC␦ to induce Bax activation, resulting in mitochondrial outer membrane leakage of apoptogenic factors such as cytochrome, following by apoptosis (81). Furthermore, reabsorption of albumin activates the GTPase Rac1 in proximal tubule cells, resulting in ROS production (147).…”

Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury

“…Recent evidence has demonstrated that proteinuria also contributes to the progression of kidney diseases (5,8). The direct effects of proteinuria on epithelial cell phenotypic transition (23), cell apoptosis (12), tubulointerstitial inflammation (2), and subsequent fibrotic response (13) may serve as the major factors in the progression of chronic kidney diseases (CKDs). However, the detailed molecular mechanisms of this pathological process remain elusive, hindering the identification of specific and effective therapeutic targets for the treatment of proteinuria-associated kidney injury.…”