The critical role of Krüppel-like factors in kidney disease

Abstract

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors critical to mammalian embryonic development, regeneration, and human disease. There is emerging evidence that KLFs play a vital role in key physiological processes in the kidney, ranging from maintenance of glomerular filtration barrier to tubulointerstitial inflammation to progression of kidney fibrosis. Seventeen members of the KLF family have been identified, and several have been well characterized in the kidney. Although they may share some overlap in their downstream targets, their structure and function remain distinct. This review highlights our current knowledge of KLFs in the kidney, which includes their pattern of expression and their function in regulating key biological processes. We will also critically examine the currently available literature on KLFs in the kidney and offer some key areas in need of further investigation.

Keywords: Krüppel-like factors; differentiation; endothelial cells; fibrosis; glomerular disease; inflammation.

Fig. 1.

Expression pattern of Krüppel-like factors in the kidney. Deep sequencing of microdissected nephron segments was performed in rat renal cortex by Lee et al. (25). From these reported findings (25), we extrapolated the Krüppel-like factors’ (KLFs) mRNA expression [reads per kilobase per million reads (RPKM)] from the expression arrays and highlighted its pattern of expression in each nephron segment. Nephron segments are as follows: G (glomeruli), S1 (1st segment of the proximal tubule), S2 (2nd segment of the proximal tubule), S3 (3rd segment of the proximal tubule), SDL (short descending limb of the loop of Henle), LDLOM (long descending limb of the loop of Henle in the outer medulla), LDLIM (long descending limb of the loop of Henle in the inner medulla), tAL (thin ascending limb of the loop of Henle), mTAL (medullary thick ascending limb of the loop of Henle), cTAL (cortical thick ascending limb of the loop of Henle), DCT (distal convoluted tubule), CNT (connecting tubule), CCD (cortical collecting duct), OMCD (outer medullary collecting duct), and IMCD (inner medullary collecting duct). Detailed methods for microdissection and RNA sequencing were previously provided (25).

Fig. 2.

Role of Krüppel-like factor 15 in podocyte differentiation. We highlight the pathway by which Krüppel-like factor 15 (KLF15) mediates retinoic acid (RA) and glucocorticoids (GCs)-induced restoration of podocyte differentiation markers [actin cytoskeleton, increased expression of podocyte-specific cytoskeleton and slit diaphragm proteins (Nephrin, Podocin, and Synaptopodin)] under cell stress. GR, glucocorticoid receptor; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element-binding protein; GRE, GC response element; CRE, cAMP response element.