Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats

Hashmat, Shireen; Rudemiller, Nathan P.; Lund, Hayley; Abais‐Battad, Justine M.; Why, Scott K. Van; Mattson, David L.

doi:10.1152/ajprenal.00594.2015

Cited by 71 publications

(52 citation statements)

References 45 publications

(61 reference statements)

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“…Previous studies using animal models of hypertension have shown that IL-6 may have a role in pathogenesis of hypertension [43,44]. Furthermore, inhibition of IL-6 was connected to attenuation of associated renal damage [45][46][47]. Thus, we believe that antihypertensive effect of linagliptin may be derived from reversing IL-6 upregulation in doxorubicin nephropathy.…”

Section: Discussionmentioning

confidence: 73%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

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Background/Aims: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. Methods: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. Results: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91^phox, p47^phox, and p67^phox in rat kidneys with doxorubicin nephropathy. Conclusion: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

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Section: Discussionmentioning

confidence: 73%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

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“…IL-6 is a proinflammatory cytokine produced by various cells including macrophages, T-lymphocytes, endothelial cells, and vascular smooth muscle cells 35 . Chronic treatment of anti-IL-6 antibody reduced salt-sensitivity and renal macrophage accumulation in SS rats 3 . Rapamycin inhibition of IL-6 expression could therefore also account for some of the anti-inflammatory effects of rapamycin 36 .…”

Section: Discussionmentioning

confidence: 94%

“…Renal inflammation is a common feature of experimental and clinical hypertension, with lymphocytes and macrophages localizing to regions of renal injury 2, 3 . In the commonly used Dahl salt-sensitive (SS) rat, it has been shown that renal inflammation amplifies the hypertension and renal damage 4, 5 , similar to observations obtained from hypertensive patients 1, 6 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats

et al. 2017

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The goal of the present study was to explore the protective effects of mTORC1 inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that H2O2 is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. Additionally, renal interstitial infusion of H2O2 into salt-resistant Sprague Dawley (SD) rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial pressure (BP). Together, these data indicate that the salt-induced increases of renal H2O2 in SS rats activated the mTORC1 pathway. Daily administration of rapamycin (i.p., 1.5 mg/Kg/day) for 21 days reduced salt-induced hypertension from 176.0 ± 9.0 to 153.0 ± 12.0 mmHg in SS rats but had no effect on BP salt-sensitivity in SD treated rats. Compared to vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0 ± 35.0 to 37.0 ± 5.0 mg/day and reduced the renal infiltration of T lymphocytes (CD3+) and macrophages (ED1+) in the cortex and medulla. Renal hypertrophy and cell proliferation was also reduced in rapamycin treated SS rats. We conclude that enhancement of intrarenal H2O2 with a 4.0% NaCl diet stimulates the mTORC1 pathway which is necessary for the full development of the salt-induced hypertension and kidney injury in the SS rat.

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“…IL-1β is closely associated with renal inflammation [48]. IL-6 has also been shown to participate in the salt-sensitive hypertension and renal injury in Dahl S rats [49]. Our results showed that high salt intake significantly increased the mRNA levels of pro-inflammatory factors IL-1β and IL-6 and that VA blocked high salt-induced increases in pro-inflammatory factors in the renal medulla in Dahl S rats.…”

Section: Discussionmentioning

confidence: 50%

Infusion of Valproic Acid Into the Renal Medulla Activates Stem Cell Population and Attenuates Salt-Sensitive Hypertension in Dahl S Rats

Wang

Zhu

Wang

et al. 2017

Cell Physiol Biochem

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Background: Our previous study has detected a stem cell deficiency in the renal medulla in Dahl salt-sensitive (S) rats. This study determined whether infusion of valproic acid (VA), an agent known to stimulate the stem cell function, attenuated salt-sensitive hypertension in Dahl S rats. Methods: Uninephrectomized Dahl S rats were infused with vehicle or VA (50mg/kg/d) into the renal medulla and fed with a low (LS) or high salt diet (HS). Stem cell marker and number were analyzed by immunohistochemistry, Real-time RT-PCR and Western blot. Sodium excretion and blood pressure were measured. Results: VA significantly increased the mRNA and protein levels of FGF2, a stem cell niche factor, and CD133, a stem cell marker. The number of CD133+ cells was significantly increased in the renal medulla in VA-treated rats. Meanwhile, high salt-induced increases in the mRNA level of proinflammatory factors interleukin-1β and interleukin-6 were blocked in VA-treated rats. Functionally, sodium excretion in response to the blood pressure increase and acute sodium loading was significantly enhanced, sodium retention attenuated, high salt-induced increase of blood pressure reduced in VA-treated rats. Conclusion: Activation of stem cell function by VA inhibits the activation of proinflammatory factors and attenuates salt-sensitive hypertension in Dahl S rats.

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Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats

Cited by 71 publications

References 45 publications

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats

Infusion of Valproic Acid Into the Renal Medulla Activates Stem Cell Population and Attenuates Salt-Sensitive Hypertension in Dahl S Rats

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