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.
Highlights
Sequence variants in MYH9 encoding myosin heavy chain 2A have been associated with two forms of kidney disease
Additional studies continue to report a correlation between intronic MYH9 polymorphisms and kidney disease in many contexts including a persistent signal for MYH9 among African-Americans with focal and segmental glomerulosclerosis (FSGS) that remains after controlling for the APOL1 G1 and G2 alleles [10], a modest association of sickle cell nephropathy with one separate and independent polymorphism each in MYH9 and APOL1 [11], a modest association of intronic MYH9 polymorphisms with diabetic nephropathy among European-Americans [12] the association of one MYH9 polymorphism with non-diabetic kidney disease in European Americans [13], and no association of IgA nephropathy with polymorphisms in either MYH9 or APOL1 [14]
The second area we addressed was whether podocyte-specific deletion of Myh9 on the C57BL/6 background results in a general susceptibility to all forms of experimental glomerular injury (a ‘‘weakened podocyte’’ effect), or whether the hypersensitivity is specific to Adriamycin nephropathy, which could arise through shared pathophysiology
Summary
Sequence variants in MYH9 encoding myosin heavy chain 2A have been associated with two forms of kidney disease. We previously reported that podocyte-specific deletion of Myh (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. Other investigators reported that podocyte-specific deletion of Myh (PodDMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. We tested C57BL/6 PodDMyh 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 Myh resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p,0.05 or less). Based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh is not absolutely required in adult podocytes
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