Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor–mediated kidney fibrosis
Jian-dong Zhang, Mehul B. Patel, Robert Griffiths, Paul C. Dolber, Phillip Ruiz, Matthew A. Sparks, Johannes Stegbauer, Huixia Jin, Jose A. Gomez, Anne F. Buckley, William S. Lefler, Daian Chen, Steven D. Crowley
Jian-dong Zhang, Mehul B. Patel, Robert Griffiths, Paul C. Dolber, Phillip Ruiz, Matthew A. Sparks, Johannes Stegbauer, Huixia Jin, Jose A. Gomez, Anne F. Buckley, William S. Lefler, Daian Chen, Steven D. Crowley
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Brief Report Nephrology

Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor–mediated kidney fibrosis

Abstract

In a wide array of kidney diseases, type 1 angiotensin (AT1) receptors are present on the immune cells that infiltrate the renal interstitium. Here, we examined the actions of AT1 receptors on macrophages in progressive renal fibrosis and found that macrophage-specific AT1 receptor deficiency exacerbates kidney fibrosis induced by unilateral ureteral obstruction (UUO). Macrophages isolated from obstructed kidneys of mice lacking AT1 receptors solely on macrophages had heightened expression of proinflammatory M1 cytokines, including IL-1. Evaluation of isolated AT1 receptor–deficient macrophages confirmed the propensity of these cells to produce exaggerated levels of M1 cytokines, which led to more severe renal epithelial cell damage via IL-1 receptor activation in coculture compared with WT macrophages. A murine kidney crosstransplantation concomitant with UUO model revealed that augmentation of renal fibrosis instigated by AT1 receptor–deficient macrophages is mediated by IL-1 receptor stimulation in the kidney. This study indicates that a key role of AT1 receptors on macrophages is to protect the kidney from fibrosis by limiting activation of IL-1 receptors in the kidney.

Authors

Jian-dong Zhang, Mehul B. Patel, Robert Griffiths, Paul C. Dolber, Phillip Ruiz, Matthew A. Sparks, Johannes Stegbauer, Huixia Jin, Jose A. Gomez, Anne F. Buckley, William S. Lefler, Daian Chen, Steven D. Crowley

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Figure 1

AT1A receptor deficiency on macrophages exacerbates kidney fibrosis induced by UUO.

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AT1A receptor deficiency on macrophages exacerbates kidney fibrosis indu...
(A) Representative kidney sections from LysM-Cre+ mT/mG mice 7 days after UUO with contralateral unobstructed kidney on left and obstructed kidney on right. (B) Polarized images of representative sections from obstructed WT and Macro KO kidneys stained with picrosirius red for collagen fibrils at day 7 after UUO. Original magnification, ×20. (C) Western blot for Col I in whole kidney at day 7 after UUO. (D) mRNA expression of ColI, Pai1, and Tgfb1 in obstructed kidney at day 7 after UUO. (E) Gene expression of M1 markers Il1b, Il1r1, Tnfa, Il12b, and Ccl2 and M2 markers Arg1, Fizz1, Ym1, and Il1r2 in obstructed kidneys at 3 and 7 days after UUO. At day 3, *P < 0.02 vs. WT, †P = 0.02 vs. WT, ‡P = 0.01 vs. WT, #P = 0.03, §P < 0.02. At day 7, *P < 0.03 vs. WT, †P = 0.02 vs. WT, #P = 0.05, §P < 0.001.