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(American Journal of Pathology. 2009;174:1291-1308.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080295

Inhibition of Autoregulated TGFβ Signaling Simultaneously Enhances Proliferation and Differentiation of Kidney Epithelium and Promotes Repair Following Renal Ischemia

Hui Geng^*, Rongpei Lan^*, Guichun Wang^*, Abdur R. Siddiqi^*, Michael C. Naski^*, Andrew I. Brooks, Jeffrey L. Barnes^*, Pothana Saikumar^*, Joel M. Weinberg and Manjeri A. Venkatachalam^*

From the Department of Pathology,^* University of Texas Health Science Center at San Antonio, San Antonio, Texas; the Department of Environmental Medicine and Genetics, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey; and the Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

We studied autocrine transforming growth factor (TGF)β signaling in kidney epithelium. Cultured proximal tubule cells showed regulated signaling that was high during log-phase growth, low during contact-inhibited differentiation, and rapidly increased during regeneration of wounded epithelium. Autoregulation of signaling correlated with TGFβ receptor and Smad7 levels, but not with active TGFβ, which was barely measurable in the growth medium. Confluent differentiated cells with low receptor and high Smad7 levels exhibited blunted responses to saturating concentrations of exogenously provided active TGFβ, suggesting that TGFβ signaling homeostasis was achieved by cell density-dependent modulation of signaling intermediates. Antagonism of Alk5 kinase, the TGFβ type I receptor, dramatically accelerated the induction of differentiation in sparse, proliferating cultures and permitted better retention of differentiated features in regenerating cells of wounded, confluent cultures. Alk5 antagonism accelerated the differentiation of cells in proximal tubule primary cultures while simultaneously increasing their proliferation. Consequently, Alk5-inhibited primary cultures formed confluent, differentiated monolayers faster than untreated cultures. Furthermore, treatment with an Alk5 antagonist promoted kidney repair reflected by increased tubule differentiation and decreased tubulo-interstitial pathology during the recovery phase following ischemic injury in vivo. Our results show that autocrine TGFβ signaling in proliferating proximal tubule cells exceeds the levels that are necessary for physiological regeneration. To that end, TGFβ signaling is redundant and maladaptive during tubule repair by epithelial regeneration.