Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy
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Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy. / Xiong, Tingting; Attar, Madena; Gnirck, Ann-Christin; Wunderlich, Malte; Becker, Martina; Rickassel, Constantin; Puelles, Victor G; Meyer-Schwesinger, Catherine; Wiech, Thorsten; Nies, Jasper F; Divivier, Mylène; Fuchs, Tobias; Schulze Zur Wiesch, Julian; Taipaleenmäki, Hanna; Hoxha, Elion; Wirtz, Stefan; Huber, Tobias B; Panzer, Ulf; Turner, Jan-Eric.
In: KIDNEY INT, Vol. 98, No. 3, 09.2020, p. 615-629.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Interleukin-9 protects from early podocyte injury and progressive glomerulosclerosis in Adriamycin-induced nephropathy
AU - Xiong, Tingting
AU - Attar, Madena
AU - Gnirck, Ann-Christin
AU - Wunderlich, Malte
AU - Becker, Martina
AU - Rickassel, Constantin
AU - Puelles, Victor G
AU - Meyer-Schwesinger, Catherine
AU - Wiech, Thorsten
AU - Nies, Jasper F
AU - Divivier, Mylène
AU - Fuchs, Tobias
AU - Schulze Zur Wiesch, Julian
AU - Taipaleenmäki, Hanna
AU - Hoxha, Elion
AU - Wirtz, Stefan
AU - Huber, Tobias B
AU - Panzer, Ulf
AU - Turner, Jan-Eric
N1 - Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - A wide spectrum of immunological functions has been attributed to Interleukin 9 (IL-9), including effects on the survival and proliferation of immune and parenchymal cells. In recent years, emerging evidence suggests that IL-9 expression can promote tissue repair in inflammatory conditions. However, data about the involvement of IL-9 in kidney tissue protection is very limited. Here, we investigated the role of IL-9 in Adriamycin-induced nephropathy (AN), a mouse model for proteinuric chronic kidney disease. Compared to wild type mice, IL-9 knockout (Il9-/-) mice with AN displayed accelerated development of proteinuria, aggravated glomerulosclerosis and deterioration of kidney function. At an early stage of disease, the Il9-/- mice already displayed a higher extent of glomerular podocyte injury and loss of podocyte number compared to wild type mice. In the kidney, T cells and innate lymphoid cells produced IL-9. However, selective deficiency of IL-9 in the innate immune system in Il9-/-Rag2-/- mice that lack T and B cells did not alter the outcome of AN, indicating that IL-9 derived from the adaptive immune system was the major driver of tissue protection in this model. Mechanistically, we could show that podocytes expressed the IL-9 receptor in vivo and that IL-9 signaling protects podocytes from Adriamycin-induced apoptosis in vitro. Finally, in vivo treatment with IL-9 effectively protected wild type mice from glomerulosclerosis and kidney failure in the AN model. The detection of increased serum IL-9 levels in patients with primary focal and segmental glomerulosclerosis further suggests that IL-9 production is induced by glomerular injury in humans. Thus, IL-9 confers protection against experimental glomerulosclerosis, identifying the IL-9 pathway as a potential therapeutic target in proteinuric chronic kidney disease.
AB - A wide spectrum of immunological functions has been attributed to Interleukin 9 (IL-9), including effects on the survival and proliferation of immune and parenchymal cells. In recent years, emerging evidence suggests that IL-9 expression can promote tissue repair in inflammatory conditions. However, data about the involvement of IL-9 in kidney tissue protection is very limited. Here, we investigated the role of IL-9 in Adriamycin-induced nephropathy (AN), a mouse model for proteinuric chronic kidney disease. Compared to wild type mice, IL-9 knockout (Il9-/-) mice with AN displayed accelerated development of proteinuria, aggravated glomerulosclerosis and deterioration of kidney function. At an early stage of disease, the Il9-/- mice already displayed a higher extent of glomerular podocyte injury and loss of podocyte number compared to wild type mice. In the kidney, T cells and innate lymphoid cells produced IL-9. However, selective deficiency of IL-9 in the innate immune system in Il9-/-Rag2-/- mice that lack T and B cells did not alter the outcome of AN, indicating that IL-9 derived from the adaptive immune system was the major driver of tissue protection in this model. Mechanistically, we could show that podocytes expressed the IL-9 receptor in vivo and that IL-9 signaling protects podocytes from Adriamycin-induced apoptosis in vitro. Finally, in vivo treatment with IL-9 effectively protected wild type mice from glomerulosclerosis and kidney failure in the AN model. The detection of increased serum IL-9 levels in patients with primary focal and segmental glomerulosclerosis further suggests that IL-9 production is induced by glomerular injury in humans. Thus, IL-9 confers protection against experimental glomerulosclerosis, identifying the IL-9 pathway as a potential therapeutic target in proteinuric chronic kidney disease.
U2 - 10.1016/j.kint.2020.04.036
DO - 10.1016/j.kint.2020.04.036
M3 - SCORING: Journal article
C2 - 32446933
VL - 98
SP - 615
EP - 629
JO - KIDNEY INT
JF - KIDNEY INT
SN - 0085-2538
IS - 3
ER -
