Podocyte-Specific Deletion of Myh9 Encoding Nonmuscle Myosin Heavy Chain 2A Predisposes Mice to Glomerulopathy

Genome-wide association studies linked single-nucleotide polymorphisms (SNPs) at theMYH9 locus to chronic kidney disease among African-Americans, particularly glomerular diseases such as HIV nephropathy and idiopathic focal and segmental glomerulosclerosis (FSGS). However, theseMYH9 SNPs are intronic, and despite extensive sequencing, a causal variant remains elusive. To investigate the role ofMYH9 in kidney disease, we selectively deletedMyh9 from mouse podocytes and found that mutant C57BL/6 mice did not develop renal insufficiency or proteinuria compared to control littermates, even when the mice were aged for 9 months. To explain the surprisingly normal phenotype, we considered genetic redundancy with the paralogMyh10 in podocytes, but we found thatMyh10 was not expressed in podocytes inMyh9 -deficient or control mice. We tested whetherMyh9 podocyte deletion predisposed mice to glomerulopathy in response to injury by doxorubicin hydrochloride (Adriamycin), and we found thatMyh9 podocyte-deleted mice developed proteinuria and glomerulosclerosis, while control mice were resistant. In summary,Myh9 podocyte deletion in C57BL/6 mice results in susceptibility to experimental doxorubicin hydrochloride glomerulopathy. We review evidence thatMYH9 dysfunction in humans results in similar susceptibility and place our data, the first examination ofMyh9 kidney disease in experimental animals, in the context of recent findings in human kidney disease, including the role ofAPOL1 .