Chronic kidney disease (CKD) is a major cause of morbidity and mortality, affecting over 10 % of the adult population. Regardless of the primary case, the progressed stage is characterized by scarring of all anatomical elements of the kidney - glomeruli, tubulointerstitium, and vasculature, referred to as renal fibrosis. Tubulointerstitial fibrosis has largely been viewed as a consequence of glomerular scarring, reflecting hypoxia downstream from the scarred glomeruli. Novel data suggest that an ongoing communication between the glomerular and tubular compartments (tubuloglomerular feedback) plays an important role in the progression of renal fibrosis. Particularly, injury to the tubular compartments leads to more pronounced glomerular injury in the future. DIE_CKD is designed to uncover the range and mechanisms of tubular injuries involved in the pathogenic tubuloglomerular feedback. To achieve the project objectives, double/quadruple transgenic mice with the possibility of time-dependent, subsequent injury to different compartments of the kidney will be used. This unique approach will enable a direct study of how the injury to tubular compartments predisposes glomeruli to more severe injury. Detailed analysis of the mechanisms behind these effects will be performed. The experimental data will be further confirmed in human renal biopsies of patients with Fabry disease with progressed CKD and renal fibrosis. Comprehensive histopathological assessment of long-term prognosis of sequential biopsies will be performed to analyze the involvement of individual compartments over time.