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hronic kidney disease dispropor- transcriptomic analysis of close to 20 leading to glomerulosclerosis and end-
tionately affects older in- organs at 6 different time points to stage renal disease. Podocytes are un-
dividuals. Such as, using the capture the proteomics and transcrip- able to proliferate and have limited
standard kidney function (estimated tional signature of aging both at organ ability to renew; therefore, >20%
glomerular filtration rate) calculations, and single-cell levels in mice.2 Not podocyte loss results in an irreversible
only 47% of people who are older than surprisingly, the kidney showed one of glomerulosclerosis and decline in
70 have normal kidney function. Several the most significant age-related glomerular filtration rate.4 Decrease in
conserved key pathways have been changes. In the kidney, there was a podocyte number provokes residual
shown to affect aging in multiple cell strong age-associated decline in the podocytes to compensate, such as
types, and they are also conserved be- number of endothelial, mesangial, and enlarging and changing their cytoarch-
tween organisms, such as anabolic loop of Henle cells. These findings itecture. Given similarities between ag-
hormone signaling (insulin and insulin- correlate with the decline observed with ing and glomerular disease, it is likely
like growth factor), chronic overactiva- glomerular filtration rate and urine- that shared pathways could play roles in
tion of the mechanistic target of rapa- concentrating capacity during aging. both.
mycin (mTOR), AMP-activated protein The investigators identified common Despite the critical role of aging in
kinase (AMPK), nicotinamide adenine gene expression changes observed in chronic kidney disease development,
dinucleotides (NAD), FOXO/sirtuins, almost every organ during aging. For limited attention has been paid to this
the resulting endoplasmic reticulum example, both tissue expression and important area in nephrology. Recent
and mitochondrial stress, cellular senes- blood levels of vascular cell adhesion reports suggested the roles of
cence, and associated inflammation.1 molecule 1 (Vcam1), periostin (Postn), endothelin-1 and renin-angiotensin
The exact molecular pathways associated and fibroblast growth factor 10 (Fgf10) system. Both pathways act via G-pro-
with aging-associated kidney disease showed a strong correlation with age. tein–coupled receptors, raise intracel-
have not been fully characterized. Genes from specific ontology groups lular calcium, and could alter the
The Tabula Muris Senis project per- such as extracellular matrix regulation, podocyte cytoskeleton and slit-
formed a comprehensive unbiased unfolded protein binding, mitochon- diaphragm. Global transcriptome anal-
drial function, and inflammatory and ysis of aging whole kidney samples
1
Renal Electrolyte and Hypertension Division, immune response showed the strongest provided limited information on the
Department of Medicine, Department of Genetics, association with aging. The in- precise transcriptome changes in
Institute of Diabetes Obesity and Metabolism, vestigators, however, noted mild differ- podocytes, due to cell heterogeneity.
University of Pennsylvania, Philadelphia, Penn- ences in the amplitude of these changes Earlier unbiased single-cell sequencing
sylvania, USA
in different organs. The kidney was one has been published for healthy adult
Correspondence: Katalin Susztak, Perelman of the organs that showed the most glomeruli, but did not include aging
School of Medicine, University of Pennsylvania, significant changes in immune cell samples.5 The Tabula Muris Senis
12-123 Smilow Translational Research Center,
3400 Civic Center Boulevard, Philadelphia,
diversity. For example, macrophages project now includes aged kidney sam-
Pennsylvania 19104, USA. E-mail: ksusztak@ with M2 subtype signature (expressing ples; however, the coverage for
pennmedicine.upenn.edu genes such as Il10, H2-Eb1, H2-Ab1, glomerular cells remains poor.2 Bulk
Pax8 are surprising as their expression for reduced kidney function and 2. Tabula Muris Consortium. A single-cell
transcriptomic atlas characterizes ageing
are considered highly specific to prox- chronic kidney disease. tissues in the mouse. Nature. 2020;583:590–
imal tubule cells. Expression of 595.
Grainyhead-like2 (Grhl2) was especially DISCLOSURE 3. Ronco P. Pathophysiology of the glomerulus:
KS serves on the scientific advisory board of KI tells the story. Kidney Int. 2020;97:5–9.
interesting, as it is an important regu- 4. Rutkowski JM, Wang ZV, Park AS, et al.
Jnana Therapeutics. The other author
lator of epithelial-to-mesenchymal declared no competing interests. Adiponectin promotes functional recovery
transition and apical and basal polar- after podocyte ablation. J Am Soc Nephrol.
2013;24:268–282.
ity, including a large number of clau- 5. Park J, Liu CL, Kim J, et al. Understanding the
ACKNOWLEDGMENTS
dins and cadherins (Figure 1), and Work in the Susztak lab is supported by kidney one cell at a time. Kidney Int. 2019;96:
therefore it could play an important 862–870.
National Institutes of Health grants R01
6. Wang Y, Eng DG, Kaverina NV, et al. Global
role in aging podocytes. DK076077, R01 DK087635, and R01 transcriptomic changes occur in aged mouse
The study has several caveats, DK105821, and by funding from the Juvenile podocytes. Kidney Int. 2020;98:1160–1173.
including the potential activation of Diabetes Research Foundation Ltd, 7. Huber TB, Edelstein CL, Hartleben B, et al.
Foundation for the National Institutes of Emerging role of autophagy in kidney
stress response genes induced by the Health, GlaxoSmithKline, Gilead, Regeneron, function, diseases and aging. Autophagy.
harsh digestion needed for podocyte Boehringer Ingelheim, Merck, and Novo 2012;8:1009–1031.
isolation. Decrease in podocyte number Nordisk. These funders and KS’s activities 8. Karaiskos N, Rahmatollahi M, Boltengagen A,
have no influence on the presented work. et al. A single-cell transcriptome atlas of the
can potentially mask the true transcrip- mouse glomerulus. J Am Soc Nephrol. 2018;29:
tional drivers of aging. Such as Fu et al.9 2060–2068.
performed bulk RNA-sequencing on REFERENCES 9. Fu J, Akat KM, Sun Z, et al. Single-cell RNA
1. Nihalani D, Susztak K. Sirt1-Claudin-1 crosstalk profiling of glomerular cells shows dynamic
isolated glomeruli and sorted podocytes regulates renal function. Nat Med. 2013;19: changes in experimental diabetic kidney
from inducible tagged NPHS2-Cre-GFP 1371–1372. disease. J Am Soc Nephrol. 2019;30:533–545.
mice and showed that podocyte marker
gene expression was decreased in disease
state. In addition, the fluorescent acti-
vated cell sorter and magnetic isolation
might have introduced a bias in cellular Moore’s law for membranous
gene expression, such as cells that did
not fit the usual podocyte prototype, for
nephropathy
example, hypertrophied or dying cells Norifumi Hayashi1,2 and Laurence H. Beck Jr2,3
might not have been used for the anal-
ysis. Single-cell analysis could be a The identification of target antigens in membranous nephropathy has
powerful tool to resolve such changes.
accelerated since the report of M-type phospholipase A2 receptor 1
Despite these weaknesses, publicly
available datasets from aging kidneys (PLA2R1). One could say that technological advances have allowed for
showed good correlation with the results the demonstration of Moore’s law (a doubling every 2 years in the
reported by Wang et al.6 number of transistors that can be fit onto a computer chip) in the field
The next steps should include func- of membranous nephropathy, and that even more antigens can be
tional validation of the identified path- expected in the near future. In this issue of Kidney International, Sethi
ways, which will necessitate the
et al. describe semaphorin-3B as a novel target antigen, defining a type
generation of novel genetically modified
animal models and correlate changes in of membranous nephropathy with onset in the pediatric population.
gene expression and phenotype devel- Kidney International (2020) 98, 1081–1084; https://doi.org/10.1016/j.kint.2020.06.020
opment such as albuminuria and Copyright ª 2020, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
glomerular filtration rate. Correlation see clinical investigation on page 1253
between mouse models and human
samples will be important to under-
I
1
Division of Nephrology, Kanazawa Medical Uni-
stand the relevance of changes observed versity, Uchinada, Ishikawa, Japan; 2Renal Sec-
t was not so long ago that there was a
in mice for our patient samples. tion, Department of Medicine, Boston University disease “entity” known as idiopathic
In summary, this study is a step School of Medicine, Boston, Massachusetts, USA; membranous nephropathy (MN)
forward to advance our understanding and 3Department of Medicine, Boston Medical defined pathologically by the membra-
Center, Boston, Massachusetts, USA nous lesion in the absence of secondary
of podocyte aging. The team has
discovered changes in developmental Correspondence: Laurence H. Beck, Jr., Renal associations. But just as all histopatho-
pathways and metabolism and inflam- Section, Department of Medicine, Boston Univer- logic lesions are now understood to
sity School of Medicine and Boston Medical Cen-
mation. Future studies shall analyze ter, 650 Albany Street, X-536, Boston,
represent a spectrum of underlying
podocyte aging in patients, as aging Massachusetts 02118, USA. E-mail: lhbeckjr@bu. etiologies at the molecular level, so too
remains the most important risk factor edu is MN. After a decades-long hunt for