Interleukin 6 Underlies Angiotensin II–Induced Hypertension and Chronic Renal Damage

Abstract

Chronic kidney disease (CKD) is a prevalent life-threatening disease frequently associated with hypertension, progression to renal fibrosis and eventual renal failure. While the pathogenesis of CKD remains largely unknown, an increased inflammatory response is known to be associated with the disease and has long been speculated to contribute to disease development. However, the causative factors, the exact role of the increased inflammatory cascade in CKD and the underlying mechanisms for its progression remain unidentified. Here we report that interleukin-6 (IL-6) expression levels were significantly increased in the kidneys collected from CKD patients and further elevated in CKD patients characterized with hypertension. Functionally, we determined that angiotensin II (Ang II) is a causative factor responsible for IL-6 induction in the mouse kidney and that genetic deletion of IL-6 significantly reduced hypertension and key features of CKD including renal injury and progression to renal fibrosis in Ang II-infused mice. Mechanistically, we provide both human and mouse evidence that IL-6 is a key cytokine functioning downstream of Ang II signaling to directly induce fibrotic gene expression and preproendothelin-1 (prepro-ET-1) mRNA expression in the kidney. Overall, both the mouse and human studies reported here provide evidence that Ang II induces IL-6 production in the kidney and that, in addition to its role in hypertension, increased IL-6 may play an important pathogenic role in CKD by inducing fibrotic gene expression and ET-1 gene expression. These findings immediately suggest the IL-6 signaling is a novel therapeutic target to manage this devastating disorder affecting millions worldwide.

IL-6 Trans-Signaling Drives Murine Crescentic GN

“…At first glance, these data are not consistent with other data describing renal benefits of IL-6 antagonism or deletion in murine lupus nephritis, 12 hyperlipidemic ApoE 2/2 mice 32 and murine NTN 33 nor with evidence that IL-6 induces or exacerbates renal disease. 11,34,35 However, at the same time yet other reports noted a protective role of IL-6 in rat NTN 9 or conversely worsening of NTN in C57Bl/6 mice by IL-6 antagonism. 10 While it certainly is conceivable that differences in the experimental design and model of renal disease accounted for some of these discrepancies, it has also been shown that IL-6 can have a dichotomous role in renal disease.…”

Left Ventricular Hypertrophy Development, Associated With Genetic Polymorphism of Inflammatory Mediators

“…В эксперименте на обезьянах показано, что носители делеции гена IL6 имеют более низкий уро-вень ангиотензина и артериального давления, а также менее выраженный нефроангиосклероз. Функцио-нально ИЛ-6 может быть связующим звеном между ангиотензином и процессами, принимающими учас-тие в развитии фиброза [8]. При этом в единственной клинической работе было показано, что генотип 174 CC достоверно реже встречался у больных ГБ, пере- несших ишемический инсульт в белой популяции Ирландии, а носительство аллеля G было ассоцииро-вано с развитием этого осложнения [9].…”

A novel approach for preventing esophageal stricture formation: olmesartan prevented apoptosis

“…By the second and third week after the caustic injury, collagen deposition begins and fibrosis followed by stricture formation may occur [2]. It is well documented that after the cell injury, the renin-angiotensin system, particularly the signaling mediated by angiotensin II receptor type I, is essential for the activation of NADPH oxidase, stimulates secretion of pro-inflammatory and profibrotic cytokines and exerts a direct mitogenic effect on fibroblasts [3,4]. Thus, we decided to investigate the putative influence of treatment with olmesartan, an AT1R blocker, on fibrosis and apoptosis in the rat model of esophageal caustic burn.…”

“…Inhibition of AT1R signaling can attenuate cellular stress and provide beneficial effects to the injured tissue [3,4]. Olmesartan (OLM) is AT1R antagonist.…”