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PIK3CA as a therapeutic target for patients with proliferative glomerulonephritis

ABSTRACT: PIK3CA as a therapeutic target for patients with proliferative glomerulonephritis

PROVIDER: PRJNA1101432 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28718293_1.fastq.gz	Fastqsanger.gz
	SRR28718293_2.fastq.gz	Fastqsanger.gz
	SRR28718294_1.fastq.gz	Fastqsanger.gz
	SRR28718294_2.fastq.gz	Fastqsanger.gz
	SRR28718295_1.fastq.gz	Fastqsanger.gz

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PIK3CA as a therapeutic target for patients with proliferative glomerulonephritis

Project description:Proliferative glomerulonephritis is a severe kidney condition often associated with advanced renal failure. Unfortunately, there is a significant lack of effective treatment options for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in glomerular epithelial cells of a patient, we demonstrate using multiple genetically engineered mouse models, single cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway in proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. In addition, we show that alpelisib, a clinically approved pharmacological PI3Ka inhibitor, improves glomerular lesions and kidney function in different models of collapsing glomerulopathy and lupus nephritis by targeting podocytes. But surprisingly, we uncovered that pharmacological inhibition of PI3Ka affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and complement deposition, all of which are characteristic features of PI3Kd inhibition. These findings were further confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Ka in proliferative glomerular lesion and show for the first time that alpelisib holds promise as a therapeutic approach that acts on both, glomerular epithelial cells and immune system.

2024-07-03 | GSE264194 | GEO

PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

Project description:Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.

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PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

Project description:PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis

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Glomerulonephritis in BXSB/MpJ-Yaa mice

Project description:Analysis of glomeruli isolated from kidneys of 4 month male BXSB/MpJ-Yaa. The BXSB/MpJ-Yaa mouse strain is a lupus-prone model. Results provide insight into the pathogenic mechanisms linked to glomerulonephritis in BXSB/MpJ-Yaa mice. The glomeruli were isolated from 6 BXSB/MpJ-Yaa (glomerulonephritis model) and BXSB/MpJ-Yaa+ (control). 6 glomerular populations of each strain were devided into 3 groups (1 group / 2 populations). 3 glomerulonephritis models versus 3 controls analysis was performed. BXSB/MpJ-Yaa is a recombinant inbred strain developed originally from a C57BL/6 female mouse and a SB/Le male mouse. Yaa (Y-linked autoimmune accelerator locus) localizing on the Y chromosome of BXSB/MpJ-Yaa male mice is the result of a duplication of an about 4 Mbp telomeric segment near the pseudoautosomal region of the X chromosome onto the Y chromosome. BXSB/MpJ-Yaa+ (control) male mice carry the wild-type Y chromosome in place of the mutant Yaa-containing Y chromosome of BXSB/MpJ-Yaa male mice.

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