Background Strain and the Differential Susceptibility of Podocyte-Specific Deletion of Myh9 on Murine Models of Experimental Glomerulosclerosis and HIV Nephropathy

Abstract

We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9flox alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p>0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p<0.05 or less). In contrast, we found that PodΔMyh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that PodΔMyh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes.

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

“…C57BL/6 nephrin Y3F/Y3F mice developed a milder and later onset phenotype than CD-1 nephrin Y3F/Y3F mice, and the phenotype was more pronounced in male versus female mice, both of which are consistent with several reports describing strain-and sex-specific differences in the severity of renal disease in genetically modified mice. [24][25][26][27][28][29][30] C57BL/6 nephrin Y3F/Y3F mice showed significant albuminuria at .6 months of age ( Figure 5A). …”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Both proteins are expressed in TECs, the latter exclusively. Mutations in both lead to renal fibrosis, and experimental studies suggest that MYH9 is important in podocyte physiology (162)(163)(164) and uromodulin in that of TECs (26,31,36,165).…”

Nonmuscle Myosin II Regulates the Morphogenesis of Metanephric Mesenchyme–Derived Immature Nephrons

“…This result is partly consistent with a previous study on podocyte-specific deletion of Myh9 on a C57BL/6 background. 26,27 These mutant mice are viable with normal kidneys under standard conditions but predisposed to drug-induced glomerulopathy. However, spontaneous glomerulosclerosis was reported on podocyte-specific Myh9 deletion on a mixed genetic background.…”