Regulation of Renal Inflammation in Chronic Kidney Disease

Regulation of Renal Inflammation in Chronic Kidney Disease

Bibliographic Details
Main Author: Khalaf, Fatimah
Language:English
Published: University of Toledo Health Science Campus / OhioLINK 2020
Subjects:
Medicine
Physiology
Cellular Biology
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=mco1588943852414778
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-mco15889438524147782021-08-03T07:15:00Z Regulation of Renal Inflammation in Chronic Kidney Disease Khalaf, Fatimah Medicine Physiology Cellular Biology Despite advances in chronic kidney disease (CKD) management strategies patients with CKD often develop oxidative stress and a pro-inflammatory state. Inflammation and oxidant stress play a central role in the onset and progression of renal injury in CKD by inducing the release of cytokines and increasing expression of adhesion molecules, which together contribute to recruitment of more inflammatory cells to the kidney, subsequently promoting a pro-fibrotic milieu. We have demonstrated that cardiotonic steroids (CTS) are significantly elevated in CKD and are important mediators of inflammation and oxidative stress in this setting. CTS enhance renal inflammation and fibrosis upon binding and signaling through the Na<sup>+</sup>/K<sup>+</sup>-ATPase, and chronically elevated levels of CTS also have deleterious effects on the progression of renal and cardiovascular disease.Paraoxonase-1 (PON-1) is a hydrolytic lactonase enzyme which is synthesized by the liver and circulates attached to high density lipoproteins (HDL). Our experimental and clinical data demonstrate an association between diminished lactonase activities of circulating PON and progression of CKD. Yet the underlying renal protective mechanism(s) are largely unknown. We have observed that renal inflammation and fibrosis are significantly increased following renal insult in animal models in which the circulating PON-1 isoform (PON-1) is knocked-out. We have also established that CTS-induced renal inflammation following renal insult is regulated by PON-1. We show that PON-1 modulates the CTS-Na<sup>+</sup>/K<sup>+</sup>-ATPase signaling axis and reduces the progression of renal inflammation, and renal impairment following renal insult. Taken together, our data suggest that PON-1 can attenuate the progression of renal inflammation in CKD and that the underlying mechanism involves attenuating the pathogenetic pathways induced by the CTS-Na<sup>+</sup>/K<sup>+</sup>-ATPase signaling axis. Our studies have shown for the first time a novel endogenous counter-regulatory mechanism of the CTS-Na<sup>+</sup>/K<sup>+</sup>-ATPase signaling activity which can be therapeutically targeted to attenuate inflammation and oxidant stress underlying renal impairment in CKD. 2020 English text University of Toledo Health Science Campus / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=mco1588943852414778 http://rave.ohiolink.edu/etdc/view?acc_num=mco1588943852414778 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Medicine
Physiology
Cellular Biology
spellingShingle Medicine
Physiology
Cellular Biology
Khalaf, Fatimah
Regulation of Renal Inflammation in Chronic Kidney Disease
author Khalaf, Fatimah
author_facet Khalaf, Fatimah
author_sort Khalaf, Fatimah
title Regulation of Renal Inflammation in Chronic Kidney Disease
title_short Regulation of Renal Inflammation in Chronic Kidney Disease
title_full Regulation of Renal Inflammation in Chronic Kidney Disease
title_fullStr Regulation of Renal Inflammation in Chronic Kidney Disease
title_full_unstemmed Regulation of Renal Inflammation in Chronic Kidney Disease
title_sort regulation of renal inflammation in chronic kidney disease
publisher University of Toledo Health Science Campus / OhioLINK
publishDate 2020
url http://rave.ohiolink.edu/etdc/view?acc_num=mco1588943852414778
work_keys_str_mv AT khalaffatimah regulationofrenalinflammationinchronickidneydisease
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