scholarly journals Gastrin, via activation of PPARα, protects the kidney against hypertensive injury

2021 ◽  
Vol 135 (2) ◽  
pp. 409-427
Author(s):  
Daqian Gu ◽  
Dandong Fang ◽  
Mingming Zhang ◽  
Jingwen Guo ◽  
Hongmei Ren ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Transcription Factor ◽  
Cell Apoptosis ◽  
Renal Fibrosis ◽  
Renal Tubule ◽  
Elevated Serum ◽  
Luciferase Reporter ◽  
Ang Ii ◽  
Tubule Cell ◽  
Renal Tubule Cell

Abstract Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

Effect of basement membrane and colloid osmotic pressure on renal tubule cell volume

1977 ◽  
Vol 233 (4) ◽  
pp. F325-F332
Author(s):  
M. A. Linshaw ◽  
F. B. Stapleton ◽  
F. E. Cuppage ◽  
J. J. Grantham
Keyword(s):  
Basement Membrane ◽  
Osmotic Pressure ◽  
Cell Volume ◽  
Cell Size ◽  
Renal Tubule ◽  
Colloid Osmotic Pressure ◽  
Outer Diameter ◽  
Tubule Cell ◽  
Cation Pump ◽  
Renal Tubule Cell

Renal tubule cell volume is thought to be kept constant by a cation pump. When active transport is blocked, intracellular impermeant solutes cause cells to swell. Cell size is then determined by transmembrane hydrostatic and colloid osmotic forces. We studied the importance of passive transmembrane forces in determining cell size in isolated rabbit proximal straight tubules (PST). We blocked active solute transport with ouabain and evaluated subsequent changes in cell size by measuring outer diameter of nonperfused tubules. Tubules in a ouabain and 6 g/100 ml protein bath swelled only 40% above control. However, removal of the tubule basement membrane with collagenase dissipated a transmembrane hydrostatic pressure and caused more swelling. Final cell volume was determined largely by bath protein concentration. Tubules in ouabain and collagenase swelled enormously in hyponcotic protein, moderately in isoncotic protein, and could be shrunk below control in hyperoncotic protein. Intracellular colloid osmotic pressure was estimated to exceed 38 cmH20. We conclude that hydrostatic and colloid osmotic forces are major determinants of cell size in isolated PST treated with ouabain.

Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension

2020 ◽  
Vol 51 (2) ◽  
pp. 119-129 ◽  
Author(s):  
Giovanna Castoldi ◽  
Raffaella Carletti ◽  
Silvia Ippolito ◽  
Massimiliano Colzani ◽  
Francesca Barzaghi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Diabetic Patients ◽  
Type I ◽  
Ang Ii ◽  
Collagen Expression ◽  
Sodium Glucose Cotransporter ◽  
Inflammatory Infiltrates

Background: Clinical trials have shown that empagliflozin (Empa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, promotes nephroprotective effects in diabetic patients. The mechanisms underlying nephroprotection are not completely known and it is not known whether the renal beneficial action is present even in non-diabetic kidney disease. The aim of this study was to evaluate the effect of Empa administration on the development of renal fibrosis in an experimental model of angiotensin II (Ang II)-dependent hypertension. Methods: Sprague Dawley rats (n = 31) were divided into 4 experimental groups. Ang II (200 ng/kg/min, osmotic minipumps, s.c., n = 9) or Ang II + Empa (10 mg/kg/day, per os, n = 10) were administered for 2 weeks. Control rats were treated with placebo (physiological saline, n = 6), and another group was treated with placebo plus Empa (n = 6) for the same period. Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental protocol. After 2 weeks, the rats were euthanized and the kidneys were excised for histomorphometric evaluation of glomerular and tubulo-interstitial fibrosis and for the immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages) and types I and IV collagen expression. Results: The administration of Ang II resulted in an increase in blood pressure (p < 0.01), glomerular (p < 0.05) and tubulo-interstitial (p < 0.01) fibrosis, renal inflammatory infiltrates (p < 0.01) and type I (p < 0.01) and type IV collagen expression (p < 0.05) compared to the control group. Treatment with Empa did not significantly modify the increase in blood pressure due to Ang II, but prevented the development of renal glomerular and tubulo-interstitial fibrosis, and the increase in inflammatory infiltrates and types I and IV collagen expression in Ang II-treated rats (p < 0.01). Conclusions: These data demonstrate that the treatment with Empa prevents the development of renal fibrosis in Ang II-dependent hypertension. In Ang II-dependent hypertension, the anti-fibrotic effect due to SGLT2 inhibition is caused by the reduction of inflammatory infiltrates and it is independent on the modulation of blood pressure increase.

scholarly journals The Effect of Chronic Progressive Nephropathy on the Incidence of Renal Tubule Cell Neoplasms in Control Male F344 Rats

2002 ◽  
Vol 30 (6) ◽  
pp. 681-686 ◽  
Author(s):  
John C. Seely ◽  
Joseph K. Haseman ◽  
Abraham Nyska ◽  
Douglas C. Wolf ◽  
Jeffrey I. Everitt ◽  
...  
Keyword(s):  
Renal Tubule ◽  
Tubule Cell ◽  
Control Male ◽  
Renal Tubule Cell ◽  
F344 Rats ◽  
Male F344 Rats

Effect of metabolic inhibitors on renal tubule cell volume

1980 ◽  
Vol 239 (6) ◽  
pp. F571-F577 ◽  
Author(s):  
M. A. Linshaw
Keyword(s):  
Cell Volume ◽  
Cell Size ◽  
Renal Tubule ◽  
Cation Transport ◽  
Metabolic Inhibitors ◽  
Cell Swelling ◽  
Tubule Cell ◽  
Bathing Medium ◽  
Cation Pump ◽  
Renal Tubule Cell

Renal tubule cell volume is thought to be kept constant by a cation pump. Ouabain, by inhibiting Na+-K+-ATPase, blocks cation transport with resultant cell swelling, but the degree of swelling is less than expected were active cation transport completely inhibited. Although the relatively rigid tubule basement membrane may limit swelling of ouabain-treated tubules, some investigators have alternatively postulated that an energy-dependent ouabain-insensitive cation pump regulates cell size. This notion derives from studies of renal cortical slices in which metabolic inhibitors such as 2,4-dinitrophenol (DNP) cause more swelling than ouabain. We blocked cellular metabolism of isolated rabbit proximal straight tubules by adding metabolic inhibitors to or removing acetate and glucose (energy substrate) from the bathing medium and evaluated subsequent changes in cell size by measuring outer diameter of nonperfused tubules. In isotonic medium, cell volume increased 36% with addition of 10(-4) M ouabain, 40% with 10(-2) M DNP, 46% with 10(-3) M cyanide, 39% with ouabain + DNP + cyanide, and 37% with removal of bath substrate (P = NS). We conclude that renal tubule cell volume is not regulated by a unique-ouabain-insensitive cation pump.

MiR-129-5p promotes radio-sensitivity of NSCLC cells by targeting SOX4 and RUNX1

2021 ◽  
Vol 21 ◽  
Author(s):  
Tongqing Xue ◽  
Gang Yin ◽  
Weixuan Yang ◽  
Xiaoyu Chen ◽  
Cheng liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Colony Formation ◽  
Nsclc Cell ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Radio Sensitivity

Background: Dysregulation of microRNAs (miRNAs) figures prominently in radio-sensitivity of non-small cell lung cancer (NSCLC). MiR-129-5p can block the development of a variety of tumors. However, whether miR-129-5p modulates radio-sensitivity of NSCLC cells remains unknown. Objective: This study was aimed to explore the role and the underlying mechanism of miR-129-5p in the radiosensitivity of NSCLC. Methods: Radio-resistant NSCLC cell lines (A549-R and H1299-R) were constructed using A549 and H1299 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to quantify miR-129-5p, SRY-box transcription factor 4 (SOX4) mRNA, and RUNX family transcription factor 1 (RUNX1) mRNA expression levels. Cell apoptosis and cell cycle were detected by flow cytometry. Cell counting kit-8 (CCK-8) assay and colony formation experiments were used to measure cell proliferation. γ-H2AX was examined by Western blot to confirm DNA injury. Dual-luciferase reporter experiments were applied to analyze the interactions among miR-129-5p, RUNX1, and SOX4. Results: In A549-R and H1299-R cells, compared with the wild type cell lines, miR-129-5p expression was remarkably reduced while SOX4 and RUNX1 expressions were increased. The transfection of miR-129-5p into NSCLC cell lines, markedly induced cell apoptosis, DNA injury, and cell cycle arrest, and inhibited cell proliferation and colony formation. RUNX1 and SOX4 were validated as target genes of miR-129-5p, and the restoration of RUNX1 or SOX4 could counteract the influence of miR-129-5p on A549-R cells. Conclusion: MiR-129-5p sensitizes A549-R and H1299-R cells to radiation by targeting RUNX1 and SOX4.

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