Decreased Nephron Number within Physiologic Ranges Increases Susceptibility to Chronic Renal Diseases Later in Life

Abstract

Background: In healthy human subjects, nephron number varies greatly between individuals and it is estimated that a normal kidney is endowed with approximately 800,000 to 1 million nephrons. Whether and to what extent a mild nephron shortage within this physiological range can increase susceptibility to CKD, has never been investigated. Methods: We studied CKD susceptibility in mice lacking Sirtuin 3 (Sirt3-/-), used as a model of mild nephron deficiency to the degree that they exhibit a 17% nephron reduction compared to wild-type littermates. Findings: In adulthood, Sirt3-/- mice do not spontaneously develop full-blown renal dysfunction, as demonstrated by comparable levels of urinary protein excretion and serum blood urea nitrogen levels, as well as a lack of signs of glomerular or tubulo-interstitial damage. However, adult Sirt3-/- mice exhibited exacerbated CKD and increased mortality following exposure to different nephrotoxic insults, namely protein overload and adriamycin. Interpretation: Our results provide evidence that even a mild reduction in nephron number is a critical determinant for increased susceptibility to CKD when the kidney is challenged by additional hits later in life. These findings suggest that any intervention to boost nephron number during active nephrogenesis may be an attractive preventive strategy for sustainably decreasing the global burden of CKD. Funding Statement: The authors stated: No funding available for the present study. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures involving animals were performed in accordance with institutional guidelines in compliance with national (D.L.n.26, March 4, 2014), and international laws and policies (directive 2010/63/EU on the protection of animals used for scientific purposes).