Periodic Reporting for period 2 - SIMPOSION (Sexual dimorphIsM in renal PrOgenitors to explain gender- Specificity In kidney physiOlogy aNd diseases)
Reporting period: 2023-02-01 to 2024-07-31
Chronic kidney disease (CKD) represents a global health burden with a prevalence >10% of the global population, projecting it to be the 5th leading cause of death by 2040. CKD can progress toward end-stage kidney disease (ESKD), requiring renal replacement therapy, i.e. dialysis and transplantation with high related risk of comorbidities and death for any cause and mostly for cardiovascular diseases.Kidney disease show a consistent sexual dimorphism. CKD progresses more fastly and kidney cancer is more frequent in males in comparison to females. By contrast, preeclampsia still represents the most frequent form of kidney disease allover the world, affecting 7% of pregnancies. The consequences of preeclampsia extend far beyond pregnancy, resulting in increased susceptibility to hypertension and CKD for the mother and the offspring. How sex influences kidney biology and cardiovascular risk is still largely unknown, with crucial gaps in CKD prevention and treatment. How sex influences kidney biology and cardiovascular risk is still largely unknown, with crucial gaps in CKD prevention and treatment.
We first identified kidney progenitors as crucial mediators of the kidney response to injury. In this project we propose that sexual dimorphism in kidney diseases may result from different response of renal progenitors to sex hormone in males and females. We also hypothesize that understanding the reason for these diversities may help unlocking crucial mechanisms for targeting preeclampsia, kidney cancer, CKD, and the related cardiovascular risk. For this reason, we plan to study the capacity of kidney progenitors to self-renew and differentiate into different kidney cell types during homeostasis and in conditions of pregnancy, ars well as in models of pre-eclampsia.
We first identified kidney progenitors as crucial mediators of the kidney response to injury. In this project we propose that sexual dimorphism in kidney diseases may result from different response of renal progenitors to sex hormone in males and females. We also hypothesize that understanding the reason for these diversities may help unlocking crucial mechanisms for targeting preeclampsia, kidney cancer, CKD, and the related cardiovascular risk. For this reason, we plan to study the capacity of kidney progenitors to self-renew and differentiate into different kidney cell types during homeostasis and in conditions of pregnancy, ars well as in models of pre-eclampsia.
1. Manuscript currently under evaluation in the journal Science.
2. A new model of preeclampsia
3. Melica ME. et al Science Translational Medicine, 2022 (discovery of a new drug to promote renal progenitors differentiation into podocytes)
4. De Chiara L. et al Nature Communications 2022 (identification of a mechanism of tubular cell response to acute kidney injury that determines survival on the short term and fibrosis and kidney disease on the long run)
5. Melica ME et al. Bioprotocols (detailed protocol for preparation of renal progenitor cultures and their differentiation into podocytes based on a new drug identified in Melica ME et al. Sci Trans Med, 2022)
2. A new model of preeclampsia
3. Melica ME. et al Science Translational Medicine, 2022 (discovery of a new drug to promote renal progenitors differentiation into podocytes)
4. De Chiara L. et al Nature Communications 2022 (identification of a mechanism of tubular cell response to acute kidney injury that determines survival on the short term and fibrosis and kidney disease on the long run)
5. Melica ME et al. Bioprotocols (detailed protocol for preparation of renal progenitor cultures and their differentiation into podocytes based on a new drug identified in Melica ME et al. Sci Trans Med, 2022)
Data obtained until this moment and currently submitted for publication show the following important new concepts:
-Estrogen-dependent generation of new podocytes from renal progenitor cells protects fertile females from glomerulosclerosis, explaining their reduced risk for chronic kidney disease in comparison to males
-The sexual dimorphism of kidney disease is linked to the female need for kidney adaptation to the increased hemodynamic and metabolic needs of pregnancy and involves estrogen-dependent function of renal progenitor cells
-Insufficient estrogen-regulated response of renal progenitors to pregnancy causes preeclampsia and fetal growth retardation, explaining also the subsequent hypertension and sensitivity to kidney disease observed in preeclamptic mothers and offspring.
- We also identified a drug, the HDAC inhibitor Panobinostat, that induced regression of proteinuria and kidney failure in mice by promoting renal progenitor differentiation into podocytes in the anti-glomerular basement membrane model (Melica ME et al. Sci Translat Med, 2022) which mimics human crescentic glomerulonephritis, with severe prognosis that represents an unmet medical need. The study was also selected for the cover of the journal.
- While analysing the acute kidney injury response in mice, we identified tubular cell polyploidy as a mechanism to recover kidney function in the early acute kidney injury phase but leading to chronic kidney disease on the long run (De Chiara L et al. Nat Comms, 2022). This revolutionizes our understanding of acute kidney injury and of acute kidney injury to chronic kidney disease transition.
Until the end of the project we also expect to clarify the mechanisms of sexual dimorphism of renal cell carcinoma and the effect of progesterone and testosterone on renal progenitor behavior.
-Estrogen-dependent generation of new podocytes from renal progenitor cells protects fertile females from glomerulosclerosis, explaining their reduced risk for chronic kidney disease in comparison to males
-The sexual dimorphism of kidney disease is linked to the female need for kidney adaptation to the increased hemodynamic and metabolic needs of pregnancy and involves estrogen-dependent function of renal progenitor cells
-Insufficient estrogen-regulated response of renal progenitors to pregnancy causes preeclampsia and fetal growth retardation, explaining also the subsequent hypertension and sensitivity to kidney disease observed in preeclamptic mothers and offspring.
- We also identified a drug, the HDAC inhibitor Panobinostat, that induced regression of proteinuria and kidney failure in mice by promoting renal progenitor differentiation into podocytes in the anti-glomerular basement membrane model (Melica ME et al. Sci Translat Med, 2022) which mimics human crescentic glomerulonephritis, with severe prognosis that represents an unmet medical need. The study was also selected for the cover of the journal.
- While analysing the acute kidney injury response in mice, we identified tubular cell polyploidy as a mechanism to recover kidney function in the early acute kidney injury phase but leading to chronic kidney disease on the long run (De Chiara L et al. Nat Comms, 2022). This revolutionizes our understanding of acute kidney injury and of acute kidney injury to chronic kidney disease transition.
Until the end of the project we also expect to clarify the mechanisms of sexual dimorphism of renal cell carcinoma and the effect of progesterone and testosterone on renal progenitor behavior.