Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI

Abstract

Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.

Keywords: acute renal failure; angiotensin; cisplatin.

Figure 1.

Stimulation of AT_1A receptors on T lymphocytes attenuates cisplatin-induced AKI. (A and B) Representative images of kidney sections from CD4-Cre⁺ mT/mG mice at 12, 24, or 72 hours after (A) saline or (B) cisplatin injection. (C–M) Renal function and injury parameters in WT (TWT) mice and CD4-Cre⁺ Agtr1a^fl/fl (TKO) mice at 72 hours after saline or cisplatin treatment. (C) BUN and (D) sCr (n=6 for saline and n≥10 for cisplatin). (E–H) Representative images of kidney sections from saline– and cisplatin–treated (E and G) TWT and (F and H) TKO mice, respectively. *Tubular dilation (mild injury); ^#lysed tubules (severe injury with cell death); ^→, loss of brush border (mild injury). (I) Semiquantitative scoring of renal pathology. (J and K) Renal mRNA expression of (J) NGAL and (K) TNF-α. (L) Serum and (M) whole–kidney TNF-α protein content. GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Figure 2.

AT_1A receptor activation on kidney epithelial cells exaggerates cisplatin nephrotoxicity. (A and B) Representative images of kidney sections from KSP-Cre⁺ mT/mG mice 72 hours after (A) saline or (B) cisplatin injection. (C) BUN and (D) sCr in saline– or cisplatin–treated WT and KKO mice (n=3 for saline and n≥33 for cisplatin). (E–G) Kidney pathology in cisplatin-treated mice. Representative images of kidney sections from cisplatin-treated (E) WT and (F) KKO mice. *Tubular dilation (mild injury); ^#lysed tubules (severe injury with cell death); ^→loss of brush border (mild injury). (G) WT and KKO kidney pathology scores (n=3 for saline and n≥12 for cisplatin). (H and I) Renal mRNA expression of (H) NGAL and (I) TNF-α. (J) Serum and (K) kidney TNF-α protein content (n=3 for saline and n≥7 for cisplatin). GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Figure 3.

The effects of AT₁ receptor blockade on cisplatin nephrotoxicity. (A) BUN, (B) sCr, and (C) kidney pathology scores in vehicle– or losartan–treated WT mice at 72 hours after cisplatin injection (n≥15).

Figure 4.

Role of TNF-α generated by the renal epithelium in the development of cisplatin–induced renal damage. (A and B) Kidney function in cisplatin–treated WT and TNF KKO (Ksp TNF KO) mice as measured by (A) BUN and (B) sCr. (C–E) Renal pathology in cisplatin-treated animals. Representative images of kidney sections from cisplatin–treated (C) WT and (D) TNF KKO mice with (E) a summary of renal injury scores (n=3 for saline and n≥17 for cisplatin). (F and G) Renal mRNA expression of (F) NGAL and (G) TNF-α (n=3 for saline and n≥9 for cisplatin). (H) Serum and (I) kidney TNF-α protein content (n=3 for saline and n=8 for cisplatin). GAPDH, glyceraldehyde-3-phosphate dehydrogenase.