Klotho is a recently discovered anti-aging gene and is primarily expressed in 
kidneys. In humans, the klotho level decreases with age whereas the prevalence 
of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the 
most common form of CKD, which leads to end-stage renal disease. A decrease in 
klotho has been found in kidneys of patients with diabetic nephropathy. The 
purpose of this study is to assess whether klotho gene deficiency affects early 
diabetic nephropathy in a mouse of model of type 1 diabetes induced by 
streptozotocin (STZ). Male KL(+/-) mutant and wild-type mice (6-8 weeks) were 
injected with multiple low doses of STZ. Renal functions and renal blood flow 
were assessed. Kidneys were collected for histological examination and molecular 
assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho 
deficiency in KL(+/-) mutant mice exacerbated STZ-induced increases in urine 
albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, 
and kidney hypertrophy, suggesting a protective role of klotho in kidney 
function and structure. Klotho deficiency did not affect renal blood flow. 
Notably, klotho deficiency significantly increased phosphorylation of Smad2, 
indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased 
phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating 
enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene 
deficiency may make kidneys more susceptible to diabetic injury. Klotho gene 
deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and 
mTOR signaling in kidneys.