Low nephron endowment increases susceptibility to renal stress and chronic kidney disease
Pamela I. Good, Ling Li, Holly A. Hurst, Ileana Serrano Herrera, Katherine Xu, Meenakshi Rao, David A. Bateman, Qais Al-Awqati, Vivette D. D’Agati, Frank Costantini, Fangming Lin
Pamela I. Good, Ling Li, Holly A. Hurst, Ileana Serrano Herrera, Katherine Xu, Meenakshi Rao, David A. Bateman, Qais Al-Awqati, Vivette D. D’Agati, Frank Costantini, Fangming Lin
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Research Article Nephrology

Low nephron endowment increases susceptibility to renal stress and chronic kidney disease

Abstract

Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated potentially novel mouse models with a 30%–70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy, followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared with controls with normal nephron number. Mice with low nephron number had reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.

Authors

Pamela I. Good, Ling Li, Holly A. Hurst, Ileana Serrano Herrera, Katherine Xu, Meenakshi Rao, David A. Bateman, Qais Al-Awqati, Vivette D. D’Agati, Frank Costantini, Fangming Lin

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Figure 3

RetUB del mice develop glomerular and tubular hypertrophy.

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RetUB del mice develop glomerular and tubular hypertrophy. (A) Top panel...
(A) Top panel, PAS-stained kidneys at 6 weeks of age show glomerular hypertrophy (imaged at 400×) in RetUB del mice. Bottom panel, quantification of glomerular surface area at 2 and 6 weeks of age. While at 2 weeks there was no difference between groups (mixed-effects regression; mice, n = 10; glomeruli, n = 1,741; P = 0.61), by 6 weeks, RetUB del mice developed glomerular enlargement, with mean glomerular surface area 1,332 μm2 larger in RetUB del compared with controls (mixed-effects regression; mice, n = 10; glomeruli, n = 1,351; P = 0.002). (B) Top panel, PAS-stained kidneys at 6 weeks of age show tubular hypertrophy (imaged at 400×) in RetUB del mice. Bottom panel, quantification of proximal tubular diameter (measured in the S3 segments) at 2 and 6 weeks of age. While, at 2 weeks, there was no difference between groups (mixed-effects regression; mice, n = 10; tubules, n = 1,000; P = 0.317), by 6 weeks, RetUB del mice developed tubular enlargement, with mean tubular diameter 7.8 μm larger in RetUB del compared with controls (mixed-effects regression; mice, n = 10; tubules, n = 1,000; P = 0.007). (C) Correlation of glomerular and tubular size with tubular diameter plotted against glomerular surface area showed that mean tubular diameter and mean glomerular surface area are highly correlated; R = 0.917. (D) RetUB del mice at 6 weeks of age have robust endolysosomal structures. Lamp1 labels exuberant and abundant late endosomes and lysosomes in RetUB del mice. Immunolabeling of N+/K+-ATPase highlights basolateral cell membranes (400× magnification). Quantification of Lamp1 fluorescence integrated density corrected for number of nuclei in proximal tubules localized to the cortex shows a significant increase in Lamp1 expression at 6 weeks of age in Ret UB del mice. *P = 0.03 using Welch’s t test; n = 3 for each group.