Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease
Jeffrey W. Pippin, Natalya Kaverina, Yuliang Wang, Diana G. Eng, Yuting Zeng, Uyen Tran, Carol J. Loretz, Anthony Chang, Shreeram Akilesh, Chetan Poudel, Hannah S. Perry, Christopher O’Connor, Joshua C. Vaughan, Markus Bitzer, Oliver Wessely, Stuart J. Shankland
Jeffrey W. Pippin, Natalya Kaverina, Yuliang Wang, Diana G. Eng, Yuting Zeng, Uyen Tran, Carol J. Loretz, Anthony Chang, Shreeram Akilesh, Chetan Poudel, Hannah S. Perry, Christopher O’Connor, Joshua C. Vaughan, Markus Bitzer, Oliver Wessely, Stuart J. Shankland
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Research Article Aging

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Abstract

With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

Authors

Jeffrey W. Pippin, Natalya Kaverina, Yuliang Wang, Diana G. Eng, Yuting Zeng, Uyen Tran, Carol J. Loretz, Anthony Chang, Shreeram Akilesh, Chetan Poudel, Hannah S. Perry, Christopher O’Connor, Joshua C. Vaughan, Markus Bitzer, Oliver Wessely, Stuart J. Shankland

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Figure 11

Anti–PD-1 antibody improves experimental FSGS.

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Anti–PD-1 antibody improves experimental FSGS. (A–D) PD-1 immunoperoxida...
(A–D) PD-1 immunoperoxidase staining (brown) of glomeruli from normal young mice (A) is increased in young mice with experimental FSGS (B). Similarly, in humans, PD-1 staining of glomeruli of a young human kidney (C) is increased in podocytes, PECs, and tubular epithelial cells of a kidney from an FSGS patient (D). Scale bars represent 50 μm. (E) Analysis of the Nephroseq data from NEPTUNE shows that PDCD1 mRNA levels in human microdissected glomeruli are significantly higher in patients with nephrotic-range versus sub-nephrotic-range proteinuria (n = 38). (F) To study PD-1 signaling in FSGS, 4-month-old mice were injected twice i.p. with a sheep anti-glomerular antibody. Mice were randomized into 2 groups, which received either an anti–PD-1 antibody (n = 8) or the isotype control IgG2a (n = 7) on days 1, 3, 6, and 10 after FSGS induction. (G–I) At the conclusion of the experiment, kidney function analyses showed that albumin/creatinine ratio (ACR) values significantly increased following FSGS induction in IgG2a control–injected but were reduced in aPD1ab-injected mice (G). Blood urea nitrogen (BUN) levels were not significantly different between the groups (H), while plasma soluble urokinase plasminogen activator receptor (suPAR) levels were significantly increased in FSGS mice injected with control IgG2a compared with young mice but were not reduced in mice injected with aPD1ab (I). (J) Quantification of podocyte density was lower in FSGS mice injected with IgG2a compared with young mice and was increased upon aPD1ab injection. (K) Glomerular scarring measured by glomerular collagen IV staining was higher in FSGS mice injected with IgG2a compared with young mice and was lowered by aPD1ab injection. (L) Nephrin immunostaining was lower in FSGS mice injected with IgG2a compared with young mice but was not significantly changed by aPD1ab injection. Each circle in J–L represents an individual glomerulus, and the number of glomeruli quantified is indicated. Statistical analysis was performed by t test.