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Sexual dimorphIsM in renal PrOgenitors to explain gender- Specificity In kidney physiOlogy aNd diseases

Objective

Kidney disorders represent a major global health burden with a significant sexual dimorphism that is largely unexplained. My group first identified the stem cells of the kidney (renal progenitors) and demonstrated their crucial role in kidney disease.
Here, I propose that sex hormones regulate number and function of renal progenitors to empower females to face the hemodynamic and metabolic challenges of pregnancy. I further propose that this process impacts on sexual dimorphisms in incidence and outcome of kidney diseases including kidney cancer. A multitude of unpublished data obtained with primary human progenitor cultures and unique mouse models of progenitor-specific sex hormones receptor knockout already support my concepts. I will demonstrate that, starting from the age of fertility, estrogen signaling in renal progenitors supports their survival and self-renewal, which is needed to increase their capacity to generate new podocytes and tubular epithelial cells. I will show that failure to produce a sufficient number of podocytes from estrogen-activated renal progenitors promotes preeclampsia and fetal growth retardation. This is a completely new pathophysiological concept of why women with a mismatch of nephron number and pregnancy-related hyperfiltration develop preeclampsia. I will further demonstrate that the same mechanism protects fertile women from severe forms of glomerular injury unrelated to pregnancy. Finally, I will prove that to compensate for the lower number of renal progenitors, testosterone pushes them to proliferate more in males and that this can explain the increased incidence of most prevalent forms of kidney cancer, that derive from renal progenitors. This topic is a direct continuation of my previous studies on renal progenitors supported by ERC Starting and Consolidator grants and will unravel fundamental paradigms in kidney physiology, adaptation, and disease with important implications for prevention and management of kidney disease.

Call for proposal

ERC-2020-ADG
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Funding Scheme

ERC-ADG - Advanced Grant

Host institution

UNIVERSITA DEGLI STUDI DI FIRENZE
Address
Piazza San Marco 4
50121 Florence
Italy
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 167 456,25

Beneficiaries (2)

UNIVERSITA DEGLI STUDI DI FIRENZE
Italy
EU contribution
€ 2 167 456,25
Address
Piazza San Marco 4
50121 Florence
Activity type
Higher or Secondary Education Establishments
AARHUS UNIVERSITET
Denmark
EU contribution
€ 129 443,75
Address
Nordre Ringgade 1
8000 Aarhus C
Activity type
Higher or Secondary Education Establishments