Podocyte Foot Process Effacement Precedes Albuminuria and Glomerular Hypertrophy in CD2-Associated Protein Deficient Mice

John M Basgen; Jenny S Wong; Justina Ray; Susanne B Nicholas; Kirk N Campbell

doi:10.3389/fmed.2021.745319

Podocyte Foot Process Effacement Precedes Albuminuria and Glomerular Hypertrophy in CD2-Associated Protein Deficient Mice

Front Med (Lausanne). 2021 Sep 10:8:745319. doi: 10.3389/fmed.2021.745319. eCollection 2021.

Authors

John M Basgen¹, Jenny S Wong², Justina Ray², Susanne B Nicholas³, Kirk N Campbell²

Affiliations

¹ Department of Research, Stereology and Morphometry Laboratory, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States.
² Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
³ Division of Nephrology, David Geffen School of Medicine at University of California, Los Angeles, CA, United States.

Abstract

Background: Podocyte foot process effacement is a key histologic finding in proteinuric kidney disease. We previously showed that 3-week old CD2AP-deficient mice have significant proteinuria, glomerular hypertrophy and mesangial expansion. The goal of this study is to use morphometry to establish the temporal sequence of podocyte foot process effacement, glomerular volume expansion and albuminuria in Cd2ap ^-/- mice by measuring these parameters at the 2-week time point. Methods: Wild-type mice age 14 ± 1 days with the Cd2ap gene (WT, N = 5) and mice deficient for Cd2ap (Cd2ap KO, N = 5) were generated. Kidneys were harvested and fixed in 2.5% glutaraldehyde and processed for examination by light and electron microscopy. An average of 415.2 (range 268-716) grid points were counted for all the glomeruli, and quantification of glomerular volume from each kidney. Urine was collected the day prior to sacrifice for urine albumin-to-creatinine ratio (ACR) measurements. Results: There was no difference in albuminuria [median (range) mg/g] between WT [212.2 (177.6-388.4) mg/g] vs. Cd2ap KO mice [203.3 (164.7-910.2) mg/g], P = 0.89; or glomerular volume 68,307[10,931] vs. 66,844[13,022] μm³, p = 0.92. The volume densities of glomerular components of the podocyte, capillary lumen and mesangium were not different for the two groups, P = 0.14, 0.14 and 0.17 respectively. However, foot process width was increased in Cd2ap KO 1128[286] vs. WT [374 ± 42] nm, P = 0.02. Conclusion: Here we show that while 2-week old WT and Cd2ap KO mice have similar levels of albuminuria, glomerular and mesangial volume, Cd2ap KO mice have more extensive podocyte foot process effacement. The data suggests that podocyte injury is the initiating event leading to mesangial expansion and albuminuria in this model.

Keywords: CD2AP deficient mice; Cavalieri Principle; Delesse Principle; albuminuria; glomerular volume; kidney morphometry; podocyte foot process effacement.