The role of GLMP in chronic kidney disease development and renal fibrosis

Worldwide chronic kidney disease represents the 12th leading cause of death and the 17th cause for loss of quality “healthy” years of life. Its prevalence is estimated to be between 8-16% of the global population. Kidney fibrosis is the pathological process common to all progressive chronic kidney diseases. We have recently generated a new knock-out mouse lacking glycosylated lysosomal membrane protein (GLMP). The absence of GLMP leads to the development of spontaneous liver fibrosis with differences versus wild type animals detectable as early as 1 week of age. This is a remarkable phenotype as it is the first description of a genetically modified strain developing spontaneous liver fibrosis. The mice grow and reproduce normally, however, with age they develop spontaneous liver cancer. GLMP is also highly expressed in kidney, hence based on the similarities in lysosomal regulation between liver and kidney, we hypothesize that lack of GLMP expression also affects the development of renal fibrosis. Two experimental models and a total number of 48 mice will be used. One model is unilateral ureteric obstruction, a widely used and accepted surgical procedure. The second model is ischemia reperfusion, also a widely used model to induce renal disease. Both procedures are classified as severity band moderate as the animals will undergo surgery. Replacement, reduction and improvement efforts have been pursued, however, the GLMP ablated mouse model is not possible to replace with simpler systems.
Chronic kidney disease is on the rise due to the aging population and the clinical complications associated with diabetes and hypertension. Therefore, there is an urgent need to increase our understanding of kidney disease pathology in order to find new therapeutic candidates for drug development.