Hypertension induces glomerulosclerosis in phospholipase C-ε1 deficiency

Area of Science:

• Nephrology
• Molecular Biology
• Genetics

Background:

• Loss-of-function mutations in phospholipase C-ε1 (PLCE1) are linked to nephrotic syndrome.
• Asymptomatic family members with PLCE1 mutations suggest additional factors are needed for disease manifestation.
• Global Plce1-deficient mice exhibit normal glomeruli and no albuminuria at baseline.

Purpose of the Study:

• To investigate the role of Angiotensin II (ANG II) in exacerbating glomerular damage in Plce1-deficient mice.
• To determine if hypertension and hyperfiltration, independent of direct ANG II effects, contribute to glomerular injury in Plce1 deficiency.

Main Methods:

• Administered ANG II to Plce1-deficient and wild-type mice to assess blood pressure, albuminuria, and glomerular histology.
• Induced hypertension using DOCA + salt + uninephrectomy and norepinephrine in Plce1-deficient mice.
• Utilized single-cell sequencing and immunohistochemistry to analyze PLCE1 expression in human and mouse kidney tissues.

Main Results:

• ANG II induced significantly higher albuminuria (20-fold) and glomerular sclerosis in Plce1-deficient mice compared to wild-type littermates.
• Plce1-deficient mice showed mesangial expansion, podocyte loss, and foot process effacement after ANG II treatment.
• Induced hypertension caused a fivefold increase in albuminuria and glomerular sclerosis in Plce1-deficient mice.
• PLCE1 transcript is highly expressed in podocytes, and Plce1 protein is found in podocytes and glomerular arterioles.

Conclusions:

• Plce1 deficiency predisposes mice to glomerular damage under hypertensive stress.
• These findings highlight the critical role of PLCE1 in podocyte protection against hypertensive insults.
• PLCE1 deficiency may represent a genetic susceptibility factor for kidney disease progression in response to environmental stressors.