Abstract
In humans and in mice the formation of nephrons during embryonic development reaches completion near the end of gestation, after which no new nephrons are formed. The final nephron complement can vary 10-fold, with reduced nephron number predisposing individuals to hypertension, renal, and cardiovascular diseases in later life. While the heterochronic genes lin28 and let-7 are well-established regulators of developmental timing in invertebrates, their role in mammalian organogenesis is not fully understood. Here we report that the Lin28b/let-7 axis controls the duration of kidney development in mice. Suppression of let-7 miRNAs, directly or via the transient overexpression of LIN28B, can prolong nephrogenesis and enhance kidney function potentially via upregulation of the Igf2/H19 locus. In contrast, kidney-specific loss of Lin28b impairs renal development. Our study reveals mechanisms regulating persistence of nephrogenic mesenchyme and provides a rationale for therapies aimed at increasing nephron mass.
Highlights
Among its many functions, the mammalian kidney removes nitrogenous waste, regulates blood volume, and maintains bone density
Nephron formation continues within an outer nephrogenic zone of the kidney until postnatal day 2 in mice[8], and the 36th week of gestation in humans[9], after which time all remaining nephron progenitors undergo a synchronous wave of differentiation to establish the final number of nephrons—the “nephron endowment”—that will persist lifelong in the adult[8]
Along with previous data showing the prevalence of LIN28B activation in human Wilms tumor[30], this strongly suggests that Lin28b plays the predominant role in normal kidney development
Summary
The mammalian kidney removes nitrogenous waste, regulates blood volume, and maintains bone density. We have recently reported that prolonged expression of Lin[28] in developing kidneys in mice markedly expands nephrogenic progenitors, blocks their final wave of differentiation, and results in neoplastic transformation resembling the most common renal neoplasm of childhood, Wilms tumor, via misregulation of let-7 miRNAs30. Both overexpression of LIN28B and knockout (KO) of let-7 miRNAs results in an upregulation of the Igf2/H19 locus that has previously been associated with the persistence of metanephric blastema in both Wilms tumor and persistent nephrogenic rests persistence of a nephrogenic mesenchyme[32] These data provide a rationale for manipulating the Lin28/let-7 pathway to prolong nephrogenesis and suggest that this approach might enable a rescue of low nephron endowment and restoration of kidney function
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