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Lai JY
; Luo J
; O'Connor C
; Jing X
; Nair V
; Ju W
; Randolph A
; Ben-Dov IZ
; Matar RN
; Briskin D
; Zavadil J
; Nelson RG
; Tuschl T
; Brosius FC 3rd
; Kretzler M
; Bitzer M
J Am Soc Nephrol
2015[Apr]; 26
(4
): 805-16
PMID25145934
show ga
TGF-?(1) is a pleotropic growth factor that mediates glomerulosclerosis and
podocyte apoptosis, hallmarks of glomerular diseases. The expression of
microRNA-21 (miR-21) is regulated by TGF-?(1), and miR-21 inhibits apoptosis in
cancer cells. TGF-?(1)-transgenic mice exhibit accelerated podocyte loss and
glomerulosclerosis. We determined that miR-21 expression increases rapidly in
cultured murine podocytes after exposure to TGF-?(1) and is higher in kidneys of
TGF-?(1)-transgenic mice than wild-type mice. miR-21-deficient
TGF-?(1)-transgenic mice showed increased proteinuria and glomerular
extracellular matrix deposition and fewer podocytes per glomerular tuft compared
with miR-21 wild-type TGF-?(1)-transgenic littermates. Similarly, miR-21
expression was increased in streptozotocin-induced diabetic mice, and loss of
miR-21 in these mice was associated with increased albuminuria, podocyte
depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21
was accompanied by increases in the rate of cell death, TGF-?/Smad3-signaling
activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4,
Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy
(n=48), albumin-to-creatinine ratio was positively associated with miR-21
expression in glomerular fractions (r=0.6; P<0.001) but not tubulointerstitial
fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-?(1) and
hyperglycemia-induced glomerular injury through repression of proapoptotic
signals, thereby inhibiting podocyte loss. This finding is in contrast to
observations in murine models of tubulointerstitial kidney injury but consistent
with findings in cancer models. The aggravation of glomerular disease in
miR-21-deficient mice and the positive association with albumin-to-creatinine
ratio in patients with diabetic nephropathy support miR-21 as a feedback
inhibitor of TGF-? signaling and functions.
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