Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells
Katharina Thomas, … , Jan Rossaint, Alexander Zarbock
Katharina Thomas, … , Jan Rossaint, Alexander Zarbock
Published September 15, 2022
Citation Information: JCI Insight. 2022;7(21):e163161. https://doi.org/10.1172/jci.insight.163161.
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Research Article Immunology Nephrology

Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells

Abstract

Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia/reperfusion injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, decreased neutrophil recruitment, and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Furthermore, the direct modulation of the Tgm2-HSP70 signalosome and reduced Ask1 activation resulted in decreased JNK activation, leading to diminished mitochondrial intrinsic apoptosis in TECs. Glutamine administration attenuated kidney damage in vivo during AKI and TEC viability in vitro under inflammatory or hypoxic conditions.

Authors

Katharina Thomas, Lisa Zondler, Nadine Ludwig, Marina Kardell, Corinna Lüneburg, Katharina Henke, Sina Mersmann, Andreas Margraf, Tilmann Spieker, Tobias Tekath, Ana Velic, Richard Holtmeier, Juliane Hermann, Vera Jankowski, Melanie Meersch, Dietmar Vestweber, Martin Westphal, Johannes Roth, Michael A. Schäfers, John A. Kellum, Clifford A. Lowell, Jan Rossaint, Alexander Zarbock

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Figure 1

Glutamine administration attenuates kidney damage and improves kidney function during IRI-induced AKI.

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Glutamine administration attenuates kidney damage and improves kidney fu...
WT mice were subjected to sham or IRI surgery and received glutamine or saline 4 hours after reperfusion. The levels of urinary protein biomarkers specific for different parts of the kidney nephron were assessed by ELISA for all time points. NGAL (A, n = 5) represents the distal tubule function; KIM-1 (B, n = 5) represents the functionality of proximal tubules. TIMP-2 and IGFBP7 (C, n = 5) are biomarkers of G1 cell cycle arrest correlating with renal tubular cell stress. Plasma creatinine (D, n = 5) as well as blood urea nitrogen levels were measured (E, n = 5). Creatinine clearance was calculated 12 and 24 hours after the procedure (F, n = 5). Renal blood flow was analyzed in the Arteria renalis (A. renalis) at baseline conditions, 4 hours and 24 hours after IRI induction (G, n = 3; mean + SD). Neutrophil recruitment into the kidney was analyzed by flow cytometry (H, n = 5). After performance of H&E staining of paraffin-embedded sections 1 tissue section per mouse was scored to identify tissue damage (I, tubular injury score; J, representative H&E staining, n = 5). Black scale bar: 100 μm; white scale bar: 50 μm. The plasma levels of CXCL1 (K), CXCL2 (L), TNF-α (M), and IL-10 (N) were analyzed by ELISA (n = 5; mean ± SEM; 1-way ANOVA *P < 0.05; **P < 0.005; ***P < 0.001).