title: 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. Although 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 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 angiotensin II-infused mice. Mechanistically, we provide both human and mouse evidence that IL-6 is a key cytokine functioning downstream of angiotensin II signaling to directly induce fibrotic gene expression and preproendothelin 1 mRNA expression in the kidney. Overall, both the mouse and human studies reported here provide evidence that angiotensin 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 that the IL-6 signaling is a novel therapeutic target to manage this devastating disorder affecting millions worldwide.
authors: Department of Biochemistry, University of Texas-Houston Medical School, Houston, TX, USA.
authors: Weiru
authors: W
authors: Zhang
authors: Wei
authors: W
authors: Wang
authors: Hong
authors: H
authors: Yu
authors: Yujin
authors: Y
authors: Zhang
authors: Yingbo
authors: Y
authors: Dai
authors: Chen
authors: C
authors: Ning
authors: Lijian
authors: L
authors: Tao
authors: Hong
authors: H
authors: Sun
authors: Rodney E
authors: RE
authors: Kellems
authors: Michael R
authors: MR
authors: Blackburn
authors: Yang
authors: Y
authors: Xia
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001706:Biopsy; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018450:Disease Progression; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006801:Humans; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009924:Organ Culture Techniques; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; C508600:IL6 protein, human; D015850:Interleukin-6; D014662:Vasoconstrictor Agents; D000804:Angiotensin II