scholarly journals CXCR4 Promotes Renal Tubular Cell Survival in Male Diabetic Rats: Implications for Ligand Inactivation in the Human Kidney

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 1121-1132 ◽  
Author(s):  
Ferhan S. Siddiqi ◽  
Li-Hao Chen ◽  
Suzanne L. Advani ◽  
Kerri Thai ◽  
Sri N. Batchu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Cell Survival ◽  
Cultured Cells ◽  
Human Kidney ◽  
Diabetic Rats ◽  
Cxcr4 Expression ◽  
Receptor Expression ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Tubulointerstitial Injury

Abstract Binding of the receptor CXCR4 to its ligand stromal cell–derived factor 1 (SDF-1) promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase 9 (MMP-9). In light of the pivotal role that the SDF-1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death. In cultured cells, CXCR4 blockade promoted tubular cell apoptosis, up-regulated Bcl-2-associated death promoter, and prevented high glucose/SDF-1-augmented phosphorylation of the pro-survival kinase, Akt. Although CXCR4 expression was also increased in biopsy tissue from patients with diabetic nephropathy, serine 339 phosphorylation of the receptor, indicative of ligand engagement, was unaffected. Coincident with these changes in receptor expression but not activity, MMP-9 was also up-regulated in diabetic nephropathy biopsies. Supporting a ligand-inactivating effect of the endopeptidase, exposure of cultured cells to recombinant MMP-9 abrogated SDF-1 induced Akt phosphorylation. These observations demonstrate a potentially reno-protective role for CXCR4 in diabetes that is impeded in its actions in the human kidney by the coincident up-regulation of ligand-inactivating endopeptidases. Therapeutically intervening in this interplay may limit tubulointerstitial injury, the principal determinant of renal decline in diabetes.

Ferroptosis involves in renal tubular cell death in diabetic nephropathy

2020 ◽  
Vol 888 ◽  
pp. 173574
Author(s):  
Yue Wang ◽  
Ran Bi ◽  
Fei Quan ◽  
Qiuhua Cao ◽  
Yanting Lin ◽  
...  
Keyword(s):  
Cell Death ◽  
Diabetic Nephropathy ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Renal Tubular

scholarly journals Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy

2010 ◽  
Vol 298 (1) ◽  
pp. F49-F61 ◽  
Author(s):  
Madhavi J. Rane ◽  
Ye Song ◽  
Shunying Jin ◽  
Michelle T. Barati ◽  
Rui Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
P38 Mapk ◽  
Caspase 3 ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Renal Tubules ◽  
Mapk Activation ◽  
Mapk Phosphorylation ◽  
Akt Phosphorylation ◽  
Akt Activation

Hyperglycemia induces p38 MAPK-mediated renal proximal tubular cell (RPTC) apoptosis. The current study hypothesized that alteration of the Akt signaling pathway by hyperglycemia may contribute to p38 MAPK activation and development of diabetic nephropathy. Immunoblot analysis demonstrated a hyperglycemia-induced increase in Akt phosphorylation in diabetic kidneys at 1 mo, peaking at 3 mo, and dropping back to baseline by 6 mo. Immunohistochemical staining with anti-pAkt antisera localized Akt phosphorylation to renal tubules. Maximal p38 MAPK phosphorylation was detected concomitant with increase in terminal uridine deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity in 6-mo diabetic kidneys. Exposure of cultured RPTCs to high glucose (HG; 22.5 mM) significantly increased Akt phosphorylation at 3, 6, and 9 h, and decreased thereafter. In contrast, p38 MAPK phosphorylation was detected between 9 and 48 h of HG treatment. Increased p38 MAPK activation at 24 and 48 h coincided with increased apoptosis, demonstrated by increased caspase-3 activity at 24 h and increased TUNEL-positive cells at 48 h of HG exposure. Blockade of p38 cascade with SB203850 inhibited HG-induced caspase-3 activation and TUNEL-positive cells. Overexpression of constitutively active Akt abrogated HG-induced p38 MAPK phosphorylation and RPTC apoptosis. In addition, blockade of the phosphatidylinositol-3 kinase/Akt pathway with LY294002 and silencing of Akt expression with Akt small interfering RNA induced p38 MAPK phosphorylation in the absence of HG. These results collectively suggest that downregulation of Akt activation during long-term hyperglycemia contributes to enhanced p38 MAPK activation and RPTC apoptosis. Mechanism of downregulation of Akt activation in 6-mo streptozotocin diabetic kidneys was attributed to decreased Akt-heat shock protein (Hsp) 25, Akt-p38 interaction, and decreased PTEN activity. Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK-mediated diabetic complications.

scholarly journals Effects of Dietary Supplementation of α-Lipoic Acid on Early Glomerular Injury in Diabetes Mellitus

2001 ◽  
Vol 12 (1) ◽  
pp. 124-133
Author(s):  
MONA F. MELHEM ◽  
PATRICIA A. CRAVEN ◽  
FREDERICK R. DERUBERTIS
Keyword(s):  
Lipoic Acid ◽  
Urinary Albumin Excretion ◽  
Diabetic Rats ◽  
Urinary Albumin ◽  
Tubular Cell ◽  
Inulin Clearance ◽  
Renal Tubular Cell ◽  
Glomerular Injury ◽  
Albumin Clearance ◽  
Renal Tubular

Abstract. Antioxidants, in particular vitamin E (VE), have been reported to protect against diabetic renal injury. α-Lipoic acid (LA) has been found to attenuate diabetic peripheral neuropathy, but its effects on nephropathy have not been examined. In the present study, parameters of glomerular injury were examined in streptozotocin diabetic rats after 2 mo on unsupplemented diets and in diabetic rats that received the lowest daily dose of dietary LA (30 mg/kg body wt), VE (100 IU/kg body wt), or vitamin C (VC; 1 g/kg body wt), which detectably increased the renal cortical content of each antioxidant. Blood glucose values did not differ among the diabetic groups. At 2 mo, inulin clearance, urinary albumin excretion, fractional albumin clearance, glomerular volume, and glomerular content of immunoreactive transforming growth factor-β (TGF-β) and collagen α1 (IV) all were significantly increased in unsupplemented D compared with age-matched nondiabetic controls. With the exception of inulin clearance, LA prevented or significantly attenuated the increase in all of these glomerular parameters in D, as well as the increases in renal tubular cell TGF-β seen in D. At the dose used, VE reduced inulin clearance in D to control levels but failed to alter any of the other indices of glomerular injury or to suppress renal tubular cell TGF-β in D. VC suppressed urinary albumin excretion, fractional albumin clearance, and glomerular volume but not glomerular or tubular TGF-β or glomerular collagen α1 (IV) content. LA but not VE or VC significantly increased renal cortical glutathione content in D. These data indicate that LA is effective in the prevention of early diabetic glomerular injury and suggest that this agent may have advantages over high doses of either VE or VC.

scholarly journals Inhibition of PDE4/PDE4B improves renal function and ameliorates inflammation in cisplatin-induced acute kidney injury

2020 ◽  
Vol 318 (3) ◽  
pp. F576-F588 ◽  
Author(s):  
Man Xu ◽  
Xiaowen Yu ◽  
Xia Meng ◽  
Songming Huang ◽  
Yue Zhang ◽  
...  
Keyword(s):  
Renal Function ◽  
Cell Survival ◽  
Tubular Cell ◽  
Pde4 Inhibitor ◽  
Renal Tubular Cell ◽  
Renal Tubules ◽  
Cisplatin Nephrotoxicity ◽  
Renal Tubular Cells ◽  
Phosphorylated Akt ◽  
Renal Tubular

Nephrotoxicity is a known clinical complication of cisplatin that limits the use of this potent antitumor drug. Cyclic nucleotide phosphodiesterases (PDEs) play complex roles in physiology and pathology. PDE4, which is a member of the PDE family, has four subtypes (PDE4A–PDE4D), and PDE4B plays an important role in inflammation. Thus, in the present study, we investigated the effect of PDE4/PDE4B inhibition on renal function and inflammation in a cisplatin nephrotoxicity model. In mice, cisplatin enhanced mRNA and protein expression of PDE4B in renal tubules. After treatment with the PDE4 inhibitor cilomilast, cisplatin-induced renal dysfunction, renal tubular injury, tubular cell apoptosis, and inflammation were all improved. Next, after silencing PDE4B in vivo, we observed a protective effect against cisplatin nephrotoxicity similar to that of the PDE4 inhibitor. In vitro, cisplatin-induced renal tubular cell death was strikingly ameliorated by the PDE4 inhibitor and PDE4B knockdown along with the blockade of the inflammatory response. Considering the known roles of some cell survival pathways in antagonizing insults, we examined levels of PDE4-associated proteins sirtuin 1, phosphatidylinositol 3-kinase, and phosphorylated AKT in cisplatin-treated renal tubular cells with or without cilomilast treatment. Strikingly, cisplatin treatment downregulated the expression of the above proteins, and this effect was largely abolished by the PDE4 inhibitor. Together, these findings indicate the beneficial role of PDE4/PDE4B inhibition in treating cisplatin nephrotoxicity, possibly through antagonizing inflammation and restoring cell survival signaling pathways.

Modulation of Renal Tubular Cell Survival: Where is the Evidence?

2006 ◽  
Vol 13 (4) ◽  
pp. 449-454 ◽  
Author(s):  
C. Lorz ◽  
A. Benito-Martin ◽  
P. Justo ◽  
A. Sanz ◽  
M. Sanchez-Nino ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Renal Tubular

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

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