Effect of renal failure and sex on gene expression in mouse strain 129S1/SvlmJ kidneys
Sex and genetic background are key, but sometimes overlooked factors, that profoundly impact disease susceptibility and presentation in both humans and disease models. We previously showed that deficiency of KLOTHO protein, an important renal regulator of mineral homeostasis and a cofactor for FGF23, causes different phenotypes in 129S1/SvlmJ (129) and C57BL/6J (B6) mouse strains (Kuro-o et al. Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 390: 45-51, 1997; Salloum JS, Garsetti DE, Rogers MB. Genetic Background Influences the Impact of KLOTHO Deficiency. Physiological Genomics. 52, 512-516 (2020). The 129 strain was more severely affected, with decreased longevity, decreased body weight, and increased amounts of kidney calcification compared to B6 mice. Here we used RNA seq to profile messenger RNAs in kidneys from control (ctrl) healthy and Klotho homozygous deficient strain 129 mice of both sexes.   The kidney messenger RNA profiles of control and Klotho homozygous deficient strain B6 mice of both sexes has been submitted separately. Comparing and contrasting the genetic architecture leading to different phenotypes associated with specific inbred mouse strains may reveal previously unrecognized and important metabolic interactions affecting chronic kidney disease.  Both sex and kidney status modulated mRNA profiles. Overall design: The Klotho mutation (Kuro-o et al. Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 390: 45-51, 1997) was made fully congenic on the 129S1/SvlmJ (129) strain by backcrossing more than 10 times. RNA was extracted from male and female mice between 44 and 54 days of age for RNA-seq profiling. Control mice with healthy kidneys were either homozygous wild type (++)  or heterozygous for the recessive Klotho mutation (Kl+).  Affected mice with renal failure were homozygous for the recessive Klotho mutation (KlKl).