Hypertension induces glomerulosclerosis in phospholipase C-ε1 deficiency

Am J Physiol Renal Physiol. 2020 May 1;318(5):F1177-F1187. doi: 10.1152/ajprenal.00541.2019. Epub 2020 Mar 30.


Loss-of-function mutations in phospholipase C-ε1 (PLCE1) have been detected in patients with nephrotic syndrome, but other family members with the same mutation were asymptomatic, suggesting additional stressor are required to cause the full phenotype. Consistent with these observations, we determined that global Plce1-deficient mice have histologically normal glomeruli and no albuminuria at baseline. Angiotensin II (ANG II) is known to induce glomerular damage in genetically susceptible individuals. Therefore, we tested whether ANG II enhances glomerular damage in Plce1-deficient mice. ANG II increased blood pressure equally in Plce1-deficient and wild-type littermates. Additionally, it led to 20-fold increased albuminuria and significantly more sclerotic glomeruli in Plce1-deficient mice compared with wild-type littermates. Furthermore, Plce1-deficient mice demonstrated diffuse mesangial expansion, podocyte loss, and focal podocyte foot process effacement. To determine whether these effects are mediated by hypertension and hyperfiltration, rather than directly through ANG II, we raised blood pressure to a similar level using DOCA + salt + uninephrectomy and norepinephrine. This caused a fivefold increase in albuminuria in Plce1-deficient mice and a significant increase in the number of sclerotic glomeruli. Consistent with previous findings in mice, we detected strong PLCE1 transcript expression in podocytes using single cell sequencing of human kidney tissue. In hemagglutinin-tagged Plce1 transgenic mice, Plce1 was detected in podocytes and also in glomerular arterioles using immunohistochemistry. Our data demonstrate that Plce1 deficiency in mice predisposes to glomerular damage secondary to hypertensive insults.

Keywords: diffuse mesangial sclerosis; glomerulosclerosis; hypertension; phospholipase C-ε1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Albuminuria / enzymology
  • Albuminuria / genetics
  • Albuminuria / physiopathology
  • Animals
  • Blood Pressure*
  • Desoxycorticosterone Acetate
  • Disease Models, Animal
  • Female
  • Glomerulonephritis / enzymology*
  • Glomerulonephritis / genetics
  • Glomerulonephritis / pathology
  • Glomerulonephritis / physiopathology
  • Hypertension / enzymology*
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Kidney Glomerulus / enzymology*
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nephrectomy
  • Phosphoinositide Phospholipase C / deficiency*
  • Phosphoinositide Phospholipase C / genetics
  • Sodium Chloride, Dietary


  • Sodium Chloride, Dietary
  • Desoxycorticosterone Acetate
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon