Protective gene proved to preserve mitochondria during the progression of kidney disease

Research by the children’s hospital for Fudan University in China has revealed that a gene called a factor of differentiation and proliferation of pancreatic progenitor cells (PPDPF) helps protect renal cells by supporting the enzymes involved in the maintenance of cellular energy levels during a chronic kidney disease.

Chronic kidney disease affects approximately 15% of the world’s population and is currently the ninth cause of death worldwide. Treatments that can slow down the progression of this condition is limited.

Association studies at the genome scale have identified nearly 800 genetic locations associated with renal function, but more than 90% of these variants are located in non -coding regions. The specific genes and the molecular mechanisms involved in a chronic kidney disease at an early stage remain incompletely understood.

The PPDPF was selected to investigate after having shown strong genomic associations with renal function in large -scale population studies.

Variants linked to a decrease in renal performance have also been associated with changes in the expression of PPDPF through several types of expression the analysis of quantitative lines (EQTL), including bulk fabric, cell type type and meta-analyzes. Although the gene has been studied in other physiological and pathological contexts, its role in kidney disease has not been tested experimentally.

In the study, “PPDPF preserves the integrity of the proximal tubule by modulating Nmnat activity in chronic kidney diseases”, published in Scientific advancesResearchers have integrated association studies across the genome on renal function and multi-ordinary analysis in order to understand the renal fibrogenesis of the first cellular events.

Kidney samples have been taken from the two mouse models and human data sets previously published to examine the activity of genes during an early stage injury.

In mouse experiences, the researchers analyzed three witness kidneys, three collected one day after an injury induced by an obstruction and two collected five days after an injury. Human data has included samples of individuals with acute kidney kidneys and pre -implantation kidney donors, drawn from single and bulk -single cell RNA sequencing data sets.

Bulk RNA sequencing and a single cell was carried out on mouse kidneys after an induced injury to follow the expression of the genes over time. Genetically modified mice without PPDPF have been developed using CRISPR-CAS9, and additional models were created by chemical exposure, surgical obstruction and aging.

Human renal data has been analyzed from existing single sequencing data games and gene expression databases. The researchers used the Knockdown and the overexpression of genes in renal cells, as well as biochemical tests to measure mitochondrial activity, Nad⁺ levels and protein interactions linked to PPDPF function.

The PPDPF has proven to be strongly expressed in healthy proximal tubular cells and increased during the early stages of renal lesion in mouse models and human samples.

The experimental loss of altered altered mitochondrial structure and function, leading to a reduction in Nad⁺ levels. Mouses devoid of PPDPF (KNOCKOUT) have developed more serious renal lesions in several models of chronic kidney disease, including those caused by aging, chemical lesions and urinary obstruction.

Supplementation with NAD⁺But not with its metabolic precursor NMN, reduces the signs of renal lesion in these mice. The overexpression of improved mitochondrial activity PPDPF, increased Nad⁺ Levels, improvement in NMNAT activity and reduces fibrosis and injury markers in kidney tissues.

According to the authors, the results suggest that “the PPDPF is a regulator of nad⁺ homeostasis involved in the modulation of CKD progression”, which strongly supports the targeting of PPDPF as potential therapy for renal fibrosis with possibilities for future chronic renal interventions.

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