P NAG 1,2, A GRIVEI 1,2, S HONG 1,2,3, K GIULIANI 1,2,4, X WANG 1,2, H HEALY 1,2,4, A KASSIANOS A1,2,4,5
1Kidney Health Service, Royal Brisbane and Women’s Hospital, Brisbane, Australia, 2Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Brisbane, Australia, 3Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, South Korea, 4Faculty of Medicine, University of Queensland, Brisbane, Australia, 5Institute of Health and Biomedical Innovation/School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
Aim: To profile adaptive/healthy versus maladaptive functioning of PTEC sourced from human CKD bio-specimen.
Background: CKD is a common chronic disease in Australia. Its progression is dependent on PTEC functioning. PTEC can: (1) undergo adaptive/healthy repair or tubular regeneration and restore kidney function; or (2) initiate a maladaptive process of cellular senescence, preventing the restoration of healthy tubular morphology and function. This concept of adaptive/healthy versus maladaptive PTEC repair predominantly based on animal models, with limited studies in human CKD
Methods: Cells from native kidney biopsies and contemporaneous urine samples were analysed by multi-colour flow cytometry to identify, enumerate and phenotype PTEC (CD10+/CD13+) for markers of repair/regeneration (glycosylated CD133, CD24, KIM-1) and cellular senescence (CD26 and senescence-associated β-galactosidase (SA-β-gal) staining).
Results: We found a significant positive correlation between reduced biopsy PTEC numbers and loss in patient kidney function (↓estimated glomerular filtration rate) and strong negative association with degree (%) of tubulointerstitial fibrosis, the histopathological hallmark of CKD. Inversely, we found significant positive correlation between urinary PTEC numbers and degree (%) of tubulointerstitial fibrosis. Furthermore, urinary PTEC expression of the regenerative marker CD24 was significantly reduced, whilst expression of senescent marker SA-β-gal was significantly elevated in patients with tubulointerstitial fibrosis compared with non-fibrotic patients.
Conclusion: Here, we show elevated urinary PTEC numbers with low regeneration phenotype is positively associated with degree of kidney tubulointerstitial fibrosis. We propose these novel diagnostic findings in urine are representative of maladaptive PTEC repair in human CKD. Further dissection of these cellular states will enable specific therapeutic targeting of maladaptive PTEC (for example, repurposing of tyrosine kinase inhibitors as senolytic agents), whilst protecting the regenerative PTEC required to restore kidney function.
Purba Nag completed her PhD in 2019, studying novel roles of DNA damage proteins Ssb1 and Ssb2 using mouse models from Griffith University, Australia. Her research interests include general cell biology, molecular biology, cell cycle, DNA damage and repair. Currently, she is doing her post-doctoral studies in Conjoint Internal Medicine Laboratory identifying novel diagnostic biomarkers of repair, regeneration and cellular senescence using kidney biopsies and urine from patients with chronic kidney diseases.